Cancer therapy that targets the Hedgehog signaling pathway considering the cancer microenvironment (Review)

  • Authors:
    • Hideya Onishi
    • Katsuya Nakamura
    • Kosuke Yanai
    • Shuntaro Nagai
    • Kazunori Nakayama
    • Yasuhiro Oyama
    • Akiko Fujimura
    • Keigo Ozono
    • Akio Yamasaki
  • View Affiliations

  • Published online on: March 18, 2022     https://doi.org/10.3892/or.2022.8304
  • Article Number: 93
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Abstract

Recently, the cancer microenvironment (CME) has received significant attention. At the local site of the tumor, cancer progression is affected by secreted cytokines and conditions derived from the CME and stimulation by cancer‑induced cytokines in an autocrine manner. The CME is characterized by various types of conditions, such as hypoxia, inflammation stimulation, and angiogenesis, and contains various components, such as reactive oxygen species, cancer‑associated fibroblasts, infiltrated immune cells, exosomes, and cancer stem cells (CSCs). These conditions and components complicate the progression of cancer. The Hedgehog (HH) signaling pathway is a morphogenesis signaling pathway that is reactivated in some cancers. In these cancers, reactivated HH signaling is involved in the induction of the malignant phenotype. HH signaling is also activated under hypoxic conditions and is considered to be strongly correlated with the CME, including the induction of cancer fibrosis and maintenance of CSCs. The aim of the present review was to elucidate a cancer therapy that targets HH signaling by considering the CME, particularly focusing on hypoxia.

How is the cancer microenvironment and Hedgehog signaling important for the cancer therapy?

The CME is an extremely special environment that favors cancer progression. The CME is characterized by various conditions, such as hypoxia and angiogenesis, and contains several components, such as cancer-associated fibroblasts (CAFs), infiltrated immune cells, and cancer stem cells (CSCs) (13). These conditions and components affect each other, establishing a cancer-specific environment. The actual conditions of the CME are complex and multifactorial. Hypoxia is considered to be an important factor in the CME. Hypoxia regulates various factors and conditions of the CME. The signaling pathways and molecules that are not activated under normoxia may be activated under hypoxia. Cancer may induce a malignant phenotype through hypoxia-activated signaling pathways, such as the Hedgehog (HH) signaling pathway, and molecules. HH signaling is involved in the CME and is activated under hypoxic conditions (4). Moreover, the contribution of HH signaling to cancer shifts from gene mutation to a ligand-dependent paracrine manner via surrounding conditions such as the CME (5). Therefore, the importance of the CME in HH signaling activation has received significant attention. Treating cancers using only a single therapeutic method is considered difficult. Various processes in cancer progression that are observed in the CME may be involved in this refractory mechanism. It is considered that an in-depth understanding of the various conditions observed in the CME and measures to prevent these conditions will contribute to the development of new effective cancer therapies for the next generation. To understand the CME, the individual factors that constitute the CME should be first elucidated.

What is the Hedgehog signaling pathway?

The HH signaling pathway is a morphogenesis signaling pathway that plays a pivotal role in growth and pattern during the embryonic period (6). However, it may be reactivated beyond the embryonic period in certain cancers, which acquire a malignant phenotype via HH signaling. Core components of HH signaling that are emphasized in the present review are the 12-transmembrane and negative regulatory receptors, Patch (PTC), 7-transmembrane protein and Smoothened (SMO), 3 Hh ligands including sonic HH (SHH), Indian HH (IHH) and desert HH (DHH), serine-threonine kinase, FUSED, suppressor of FUSED (SUFU), and the 3 transcriptional factors, glioma-associated oncogene (GLI)1, GLI2 and GLI3. In the absence of HH ligands, PTC inhibits SMO and GLIs form huge complexes with FUSED and SUFU. Therefore, GLIs cannot translocate to the nucleus, and the signal does not transduce. In contrast, in the presence of HH ligands, SMO is released from the inhibition of PTC, and then, GLIs can be released from the complex. Thereafter, GLIs can translocate to the nucleus, and signaling is successfully transduced. Target genes of HH signaling include GLI1 and PTC1. Therefore, GLI1 is considered to be an index of HH signaling activation (7). Fig. 1 shows an outline of HH signal transduction. The mechanism of reactivation of HH signaling in cancers is considered to be gene mutation. For example, there are certain reports of gene mutations in HH signaling in basal cell carcinoma (8), medulloblastoma (9), rhabdomyosarcoma (10) and glioblastoma (11). After 2003, ligand-dependent HH signaling activation, but not gene mutation, has been reported. For example, SHH secreted in an autocrine or paracrine manner from the CME activates HH signaling in pancreatic cancer (12), colon cancer (13), hepatocellular carcinoma (HCC) (14), lung (15), ovarian (16), gastric (17) and prostate cancer (18). Previously, it was revealed that SHH, from monocytes that exist in pancreatic cancer stroma, activates HH signaling in pancreatic cancer to induce proliferation (19). HH signaling activation by SHH secreted from the adjacent tissue is a more severe problem than gene mutation from the viewpoint of the high probability of induction of HH signaling activation. This may also be a reason why determining the association between the HH signaling pathway and the CME is important.

Hypoxia

Molecules and signaling pathways that are activated under hypoxia

Cancer hypoxia is an important characteristic of the CME. Hypoxia is ordinally investigated under 20% O2 conditions, however, 20% O2 conditions do not exist in vivo. The O2 saturation of all human tissues is ~1% O2, and cancer tissue is particularly hypoxic (O2 saturation, ~0.1%) (20). The molecules and signaling pathways that are not activated under normoxic conditions may be activated under hypoxic conditions. To determine the cancer phenotype under hypoxic cancer conditions, 1% O2 is used in experiments. It has been previously reported that activation of HH signaling is upregulated under hypoxic conditions (4). In the present study, SMO transcription increased under hypoxic conditions. A similar result was reported by Lei et al (21). In the analysis of the mechanism underlying the increase in SMO expression under hypoxia, the upstream molecules of SMO were analyzed and two molecules, recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3), were detected (22). RBPJ and MAML3 have recently been found to be a transcriptional factor and a coactivator of Notch signaling, respectively (23). The Notch signaling pathway is also a morphogenetic signaling pathway. Our previous study on pancreatic cancer cell lines revealed that hypoxia increases the expression of RBPJ and MAML3 and contributes to the transcription of SMO (22). This RBPJ/MAML3/SMO signaling pathway is also activated in small-cell lung cancer (24). The RBPJ/MAML3/SMO signaling may be a comprehensive therapeutic target for morphogenesis signaling. Hypoxia-inducible factor (HIF)-1a is an important transcriptional factor that plays a pivotal role in various cell functions such as cell proliferation, survival, apoptosis, and angiogenesis under hypoxia. No correlation or crosstalk was observed in RBPJ/MAML3/SMO signaling in our previous study (22). However, numerous studies have shown a correlation between HIF-1α and HH signaling. Considering that HIF-1α regulates HH signaling as an upstream mediator, it was demonstrated that fibroblast growth factor receptor-like-1 (FGFRL1) expression is induced by HIF-1α and that it promotes tumor progression by crosstalk with HH signaling in ovarian cancer (25). Mitochondrial glutamic pyruvate transaminase was revealed to promote tumorigenesis and stemness of breast cancer cells by activating HH signaling via HIF-1α (26). In addition, it has been reported that natural agents contribute to the interaction between HIF-1α and HH signaling. Resveratrol, which is extracted from various plants, decreased HIF-1α expression and inhibited HH signaling to decrease invasiveness in gastric cancer cells (27). Oroxylin A, a bioactive flavonoid, induced HIF-1α degradation and led to the inactivation of HH signaling to increase the sensitivity of glioma cells to temozolomide (28). Curcumin has an inhibitory effect on HIF-1α, decreasing proliferation in breast cancer (29), and curcumin was revealed to suppress hypoxia-induced endothelial-mesenchymal transition (EMT) by inhibiting HH signaling in pancreatic cancer cells (30). HIF-1a protects cancer cells from radiation-induced apoptosis (31). Furthermore, curcumin has been shown to increase the efficiency of g-irradiation in glioma by suppressing HH signaling (32). This suggests that the curcumin-induced decrease of HIF-1α may lead to inactivation of HH signaling and consequently suppression of cancer cell function. Conversely, HH signaling has been reported to regulate HIF-1α. In a previous study, inhibition of HH signaling suppressed hepatic stellate cells through inhibition of HIF-1α and heat shock protein 90 (33).

Correlation of hypoxia with other morphogenesis signaling pathways

Other morphogenesis signaling and HH signaling pathways have been associated to the CME. The correlation between hypoxia and Wnt/b-catenin signaling has been well elucidated. Among the three subunits of HIF (HIF-1α, 2α and 3α), the contribution of HIF-2α in tumor progression is well reported in Wnt/β-catenin signaling (34). Inhibition of HIF-2α leads to decreased expression of β-catenin and SMAD4 and suppresses the progression to high-grade mPanINs (35). However, the precise contribution of hypoxia to Notch signaling activation has not been clearly reported. As previously described, hypoxia induces the expression of RBPJ and MAML3 (22). Considering that RBPJ is a transcriptional factor for Notch signaling and MAML3 is a transcriptional mediator of Notch signaling, Notch signaling should be activated under hypoxia. Moreover, RBPJ and MAML3 may regulate HH signaling and Notch signaling concurrently. RBPJ and MAML3 could be new comprehensive therapeutic targets for morphogenesis signaling. In another study, activated Notch1 markedly increased the transcriptional activity of HIF-1 (36). In choriocarcinoma cells, it has been shown that HIF-1α promotes invasiveness through Notch signaling activation (37). These results explain the association between hypoxia and Notch signaling. FGF signaling is also a type of morphogenesis signaling. Although a direct correlation between hypoxia and FGF signaling has yet to be demonstrated, hypoxia is involved in the activation of different signaling pathways in FGF-2-stimulated human microvascular endothelial cells, which may contribute to hypoxia-induced angiogenesis (38). FGF signaling is also a key pathway in HCC (39). Therefore, FGF signaling plays an important role in the progression of cancer in the CME.

Acidosis and reactive oxygen species (ROS)

Acidosis and ROS are among the most characterized properties of the CME. Hypoxic conditions are considered to induce ROS generation and cause acidosis. Acidosis also induces ROS generation (40). ROS contribute to transformation, survival, proliferation, invasion and metastasis of cancer cells (41). Although the correlation between acidosis and HH signaling has not been fully elucidated, it has been shown that ROS promotes HIF-1α stabilization to induce HH signaling activated-cancer cell proliferation (42). Other studies have revealed that ROS inhibitors block GLI1-dependent EMT and invasion under hypoxia (43) and that resveratrol suppresses hypoxia-induced ROS-mediated invasiveness and migration in pancreatic cancer via inhibition of HH signaling (44).

Reoxygenation

Reoxygenation is an important process in the CME. It is considered to be the process by which cancer cells detach from hypoxic cancers and metastasize to secondary tissues through the bloodstream. HH signaling may contribute to cancer progression during reoxygenation. In a previous study, pancreatic cancer cells increased proliferation and invasion during the reoxygenation process through HH signaling activation using the chronic hypoxia-resistant pancreatic cancer cells that were generated (45). Consistent with this result, it has been reported that the activation of HH signaling protects cell apoptosis and cell viability from reoxygenation stress in noncancerous H9C2 myocardial cells and HK-2 cells in experiments assuming the clinical situation of ischemia (46,47). Therefore, reoxygenation-induced HH signaling activation may be required for tissue repair. Cancer may utilize this nature of HH signaling during the reoxygenation process.

Angiogenesis

Cancer adapts to hypoxic conditions by inducing the formation of new blood vessels, which is called angiogenesis. Angiogenesis is implicated in hypoxia. Angiogenesis-related genes include vascular endothelial growth factor (VEGF), VEGF receptor, basic FGF (bFGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), adrenomedullin, and epidermal growth factor (EGF); these genes are targets of HIF (48).

HH signaling contributes to vasculature development, differentiation, and maintenance during the embryonic period (49). Canonical HH signaling has been reported to regulate hepatic stellate cell-induced angiogenesis in liver fibrosis (28). Yang et al (50) have revealed that HH signaling, prospero-related homeobox 1, and HIF-1α contribute to liver sinusoidal endothelial cell angiogenesis. Considering this fact, HH signaling appears to affect vasculature development even in cancer tissues. The association between HH signaling and VEGF has been reported in several types of cancers, such as HCC (51) and colorectal cancer (52). The association between HH signaling and bFGF has been reported (53), and it may also be related to cancer fibrosis induced by HH signaling, as described below. The association between HH signaling and PDGF (54), IGF (55), and EGF (56) has also been reported. Bausch et al (57) have shown that SHH stimulates angiogenesis indirectly through other pathways, including the reduction of antiangiogenic thrombospondin 2 and tissue inhibitor of metalloproteinase 2 in stromal cells in pancreatic cancer. Thus, angiogenesis, hypoxia, and HH signaling are well correlated.

Cancer fibrosis

Cancer fibrosis is an important process and a complication in which cancer acquires the refractory phenotype. The association between HH signaling and fibrosis has been implicated in chronic lung fibrosis in 2003 (58) and biliary fibrosis in chronic cholecystitis in 2008 (59). Fibrosis is marked in pancreatic cancer, and desmoplasia has been investigated. HH signaling has been reported to promote desmoplasia in pancreatic cancer in 2008 (60). Recently, it was demonstrated that the increased secretion of SHH through HIF-1α signaling is responsible for the cancer fibrosis or the stroma-rich environment in pancreatic cancer (61,62). A severe case of cancer fibrosis in the CME may block the circulation of chemotherapeutic agents and infiltration of immune cells. Olive et al (63) have revealed that inhibition of HH signaling enhances the delivery of chemotherapy in a pancreatic cancer mouse model. In our xenograft experiments using pancreatic cancer cell lines and CAFs, inhibition of cancer fibrosis by HH inhibition led to an increase in tissue-infiltrating lymphocytes and an enhancement of the effect of immune checkpoint inhibitors (64). However, Steele et al (65) have shown that inhibition of HH signaling reduces myofibroblastic CAFs and increases inflammatory CAFs to decrease cytotoxic T-cell infiltration and expand regulatory T (Treg) cells. There are few studies on infiltration of dendritic cells (DCs) and macrophages related to cancer fibrosis. However, some researchers have shown that macrophage infiltration induces fibrosis. Xue et al (66) revealed that macrophages promote pancreatic fibrosis in chronic pancreatitis, and Ueshima et al (67) demonstrated that macrophage-secreted transforming growth factor (TGF)-1 contributes to fibroblast activation. Cancer fibrosis consists of CAFs and an extracellular matrix that secretes various cytokines. One of the most important cytokines is TGF-β. Fibrosis is a typical pathological condition of TGF-β-driven disease (68). The TGF-β/SMAD cascade is considered to be a potent inducer of GLI2 (69). Therefore, in the presence of TGF-β, it may induce cancer fibrosis and activate HH signaling, which may lead to more fibrosis. Zhou et al (70) showed that HH signaling and TGF-β1 contribute to the progression of fibrosis in nonalcoholic steatohepatitis. A previous study revealed the association among TGF-β, fibrosis, and HH signaling, particularly in liver fibrosis, and GANT61, a GLI inhibitor, has been shown to be effective for liver fibrosis (71). Both HH signaling and TGF-β in the CME may play an important role in cancer fibrosis.

Immune cells

As aforementioned, the CME is closely correlated with hypoxia and HH signaling activation. Therefore, the functions of immune cells such as lymphocytes, macrophages, DCs, myeloid-derived suppressor cells (MDSCs), and Treg cells that infiltrate local cancer sites should be considered with regard to these factors.

Association to hypoxia

It has been shown that hypoxic stress increases the cytotoxicity of CD8+ T cells and decreases their proliferative and differentiating capacities (72). Consistent with this result, in our previous study, proliferation of activated lymphocytes decreased under hypoxia, but there was no significant change in their migration (73). The function of DCs is also altered under hypoxia. The duration of hypoxic exposure may affect the DC response and continuous vs. intermittent hypoxia (74). The motility and phagocytic ability of hypoxia-induced DCs are significantly lower than those of normoxia-induced DCs. Maturation of hypoxia-induced immature DCs is more suppressed than that of normoxia-induced immature DCs due to their decreased motility and phagocytosis (75). In addition, previous studies have shown that the cross-linking of triggering receptors expressed on myeloid cells-1 under hypoxia is associated with an induced release of inflammatory cytokines and chemokines in DCs (76,77). With respect to immune-suppressing cells, it has been reported that hypoxia induces CCL28 to recruit Treg cells at the local site of the cancer (78). It has also been revealed that hypoxia enhances immunosuppression by promoting immunosuppressive capacities of Treg cells (79). Similarly, hypoxia induces MDSC recruitment through CCL26 in HCC (80). It has been identified that HIF-1α regulates the function and differentiation of MDSCs within the hypoxic CME (72). HIF-1α plays a pivotal role in macrophage-mediated inhibition of T cells under hypoxia (81). Macrophages also upregulate the expression of matrix metalloproteinase-7 in hypoxic tumor cells to protect tumor cells from the cytotoxic activity of natural killer cells and T cells (82,83). In a study by Sureshbabu et al (84), hypoxia-exposed γδT cells exhibited reduced cytotoxicity in oral tumor cells. Thus, hypoxia mainly supports the immunosuppressive function of immune cells.

Association to HH signaling

HH signaling contributes to the function of activated lymphocytes, such as migration, proliferation and cytotoxicity (73). T-cell receptor activation triggers the expression of HH signaling components, and HH signaling is required for cytotoxic T lymphocyte (CTL) killing (85). Conversely, certain researchers have shown that HH signaling promotes tumor-associated macrophage polarization to inhibit tumor-infiltrated CD8 T-cell recruitment (86) and that HH signaling promotes Th2 differentiation in naive human CD4 T cells (87). Other researchers have shown that GLI1 induces the polarization of invading myeloid cells to MDSCs (88). These results indicated that HH signaling is required for lymphocyte function and immune response in both activation and inhibition. HH signaling is also involved in the functions of DCs, including induction, migration, chemotaxis, phagocytosis, maturation, and IL-12 p40 or p70 secretion and the allogeneic lymphocyte stimulation activity of monocyte-derived DCs (89). The association between hypoxia and HH signaling may determine the functions of immune cells.

Correlation between the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis and the CME

Previously, the concept of immune checkpoints has received significant attention. There are patients who are not eligible to receive standard therapy due to their drug tolerance and achieve complete response by immune checkpoint inhibitor treatment (90). Thus, studies on the PD-1/PD-L1 axis are considered important. It has been shown that PD-L1 is a direct target of HIF-1α (91). Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function (92). Tumors may escape immune cells by regulating the PD-1/PD-L1 axis under hypoxic conditions. However, it has been shown that HH signaling induces PD-L1 expression in gastric cancer (93) and that HH inhibition leads to a decrease in PD-L1 expression under hypoxia in pancreatic cancer (94). Previously, it has been shown that soluble PD-1/PD-L1 or exosomal PD-L1 plays an important regulatory role in antitumor immunity (95,96). Development of a measure against the enhanced PD-1/PD-L1 axis should be the next strategy for cancer therapy. With respect to the other factors of the CME, lymphocytes secrete INF-γ, which induces PD-L1 when lymphocytes infiltrate the cancer tissue (97). A previous study has shown that PD-L1 expression is associated with tumor-infiltrating lymphocytes in squamous cell cervical carcinoma (98). However, it is unclear whether lymphocyte infiltration into cancer tissue is the cause or result of PD-L1 expression. In addition, although PD-L1 is considered to be an exhaustion marker (99), the significance of PD-L1 expression as a biomarker for immunotherapy is controversial.

Autophagy

Autophagy is a cellular self-degradation process that maintains homeostasis using this system. Autophagy is involved in the initiation, progression, and drug resistance of cancers (100); therefore, autophagy is considered a target for cancer therapy. Hypoxia and metabolic stress upregulate autophagy (101). Autophagy and hypoxia-upregulated HH signaling appear to be correlated, and the association between autophagy and HH signaling has been well elucidated (102,103). However, it is unclear whether HH signaling inhibits or upregulates cancer autophagy. The SMO antagonist vismodegib was demonstrated to trigger marked autophagy in non-small cell lung cancer (104), while the GLI1/2 inhibitor GANT61 induced autophagy in HCC (105). Milla et al (102) have shown that the HH antagonist cyclopamine prevents autophagy. Further, Gagné-Sansfaçon et al (106) have revealed that loss of HH signaling leads to a decrease in autophagy in the intestinal ileum. Therefore, it is deemed that the contribution of HH signaling to autophagy warrants further investigation, considering the fact that there is crosstalk between HH signaling and other signaling pathways.

Cancer stem cells

Increasing evidence suggests that the host microenvironment plays a pivotal role in CSC status (107). For example, hypoxia promotes stem-like properties of laryngeal cancer cells (108) and is closely associated with the resistance of CSCs to chemotherapy and radiotherapy (109). Hypoxia enhances the expression of the CSC transcription factors NANOG, Oct4, SOX2 and CD133 (110). Multiple secreted cytokines and growth factors in the CME induce the enrichment of CSCs in ovarian cancer (111). As with other CME factors, nutritional stress in the microenvironment induces increased expression of glioblastoma CSC-specific biomarkers with higher invasiveness and angiogenesis through Wnt/HH signaling (112). In addition, numerous studies have shown that morphogenesis signaling is important for the maintenance of CSCs. For example, in an experiment on breast cancer, the HH signaling pathway was activated in the CD24−/low CD44+ CSC population, but not in the CD24+ CD44+ non-CSC population, and HH signaling inhibition in the CD24−/low CD44+ CSC population attenuated tumor proliferation (113). Notch signaling contributes to endocrine resistance in breast cancer through the promotion of the CSC phenotype (114). Notch inhibitors increase the chemotherapy effect through CD133+ CSC inhibition in endometrial cancer (115). Inhibition of Wnt/β-catenin signaling is considered to decrease the aggressiveness of breast cancer through CSC inhibition (116). Wnt/β-catenin signaling contributes to CSC-initiated HCC (117). Bone morphogenetic protein (BMP)/TGF-β signaling, which is a morphogenesis signaling pathway, contributes to the homeostasis of neural and glioma stem cells (118). The correlation between Notch signaling and BMP/TGF-β signaling has also been reported (119).

Exosomes

Exosomes are extracellular microvesicles measuring 30–100 nm in diameter, are actively secreted through an exocytosis pathway by various cell types (120,121), and comprise a nucleic acid and protein derived from secreted cells. Exosomes are significantly rigid and resistant to enzymatic degradation; therefore, they are considered to play a pivotal role in cell-to-cell interactions in the CME. Deep and Panigrahi (122) have reported that exosomes mediate tumor microenvironment remodeling, such as angiogenesis, EMT, metastasis, survival, proliferation, metabolism, stemness, and therapeutic resistance under hypoxic conditions through several signaling pathways, including the HH signaling pathway. Even during the morphogenesis period, exosomes are required for the distribution of morphogenes, such as HH ligands (123). In relation to HH signaling and CSC, it has been shown that exosomes derived from human bone marrow mesenchymal stem cells promote the growth of osteosarcoma and gastric cancer through HH signaling (124). CSC-derived exosomes contain stemness-specific proteins, self-renewal-promoting miRNAs, and survival factors, and they play a significant role in tumor heterogeneity and tumor progression (125). HH pathway proteins, including PTC1, SMO, and SHH, are exported to the cervical cancer cell line (126). SHH is highly expressed in CAFs, and CAF-derived exosomes contribute to the augmentation of growth and progression in esophageal squamous cell carcinoma (127). With respect to the association between exosomes and CME, Wada et al (128) have shown that TGF-β1 expressed on the surface of cancer ascites-derived exosomes is involved in the maintenance of the number and suppressive function of Treg cells. Matsumoto et al (129) have shown that dendritic cell-derived exosome supports CD4+ T cell survival. Taken together, exosomes play a pivotal role in the maintenance of CME.

Nuclear transcription factor-κΒ

Local cancer sites often arise from inflammation. Inflammation is closely related to the CME and is required for the initiation of immune cell activation. Nuclear transcription factor (NF)-κB is an important transcriptional factor that regulates inflammation (130). The association between SHH and NF-κB has been mainly reported. In a previous study, NF-kB was shown to contribute to the initiation of chronic pancreatitis and be involved in cancer initiation through SHH expression in pancreatic cancer (131). A similar finding was reported by Kasperczyk et al (132). The correlation between SHH and NF-κB has been revealed in multiple myeloma (133). SHH is secreted by tumor-infiltrated macrophages through the NF-κB pathway and induces proliferation in a paracrine manner in pancreatic cancer (19). The contribution of NF-κB to cancer-infiltrated lymphocytes has also been reported (134). Collectively, NF-κB significantly contributes to the CME.

Future directions

In the present review, the individual factors that constitute the CME have been described, focusing on hypoxia and HH signaling. As previously described, these factors are correlated and form the CME (Fig. 2). Inhibitors of each factor have been developed, and the mechanisms involved should be understood considering the complex correlation among the factors. Fosko et al (135) have revealed that vismodegib exhibited 60% response in basal cell carcinoma regardless of the histopathologic subtype. On the other hand, a phase 2 trial using the SMO inhibitor vismodegib with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma did not show a significant effective result (136). This trial had difficulties in analyzing the specimens before and after chemotherapy; the cause of the failure was not clear. Previous studies have shown that SMO mutation in cancer cells affects the effects of vismodegib (137,138). Thus, although HH inhibitors have exhibited a significant tumor suppressive effect in vitro (139), this effect has not always been observed in vivo. It was hypothesized that this discrepancy may be due to the difficulty in obtaining similar results with human CME as in in vitro and in vivo mouse experiments.

The therapy that targets only one CME factor may not be sufficient for cancer treatment. If the correlation among these CME factors can be substantiated, each CME inhibitor can be used effectively for cancer therapy. In Fig. 2, an overview of the correlation among hypoxia, HH signaling and other CME factors is demonstrated. Each factor individually plays a pivotal role in the formation of the CME. The correlated factors constitute the CME and contribute to cancer progression.

Acknowledgements

The authors would like to thank Ms. Emi Onishi (Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University) for her skillful technical assistance.

Funding

The present study was supported by the Japan Society for the Promotion of Science KAKENHI (grant nos. JP19K22662, JP19K09124, JP19K09047 and JP21K08712).

Availability of data and materials

The datasets used and/or analyzed are available from the corresponding author on reasonable request.

Authors' contributions

HO, KatN and KY wrote the manuscript. SN, KazN and YO designed the manuscript. AF, KO and AY selected the references. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Balkwill FR, Capasso M and Hagemann T: The tumor microenvironment at a glance. J Cell Sci. 125:5591–5596. 2012. View Article : Google Scholar : PubMed/NCBI

2 

Rakhshandehroo T, Smith BR, Glockner HJ, Rashidian M and Pandit-Taskar N: Molecular immune targeted imaging of tumor microenvironment. Nanotheranostics. 6:286–305. 2022. View Article : Google Scholar : PubMed/NCBI

3 

Wang M, Zhao J, Zhang L, Wei F, Lian Y, Wu Y, Gong Z, Zhang S, Zhou J, Cao K, et al: Role of tumor microenvironment in tumorigenesis. J Cancer. 8:761–773. 2017. View Article : Google Scholar : PubMed/NCBI

4 

Onishi H, Kai M, Odate S, Iwasaki H, Morifuji Y, Ogino T, Morisaki T, Nakashima Y and Katano M: Hypoxia activates the hedgehog signaling pathway in a ligand-independent manner by upregulation of Smo transcription in pancreatic cancer. Cancer Sci. 102:1144–1150. 2011. View Article : Google Scholar : PubMed/NCBI

5 

Onishi H and Katano M: Hedgehog signaling pathway as a therapeutic target in various types of cancer. Cancer Sci. 102:1756–1760. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Ingham PW and McMahon AP: Hedgehog signaling in animal development: Paradigms and principles. Genes Dev. 15:3059–3087. 2001. View Article : Google Scholar : PubMed/NCBI

7 

Low JA and de Sauvage FJ: Clinical experience with hedgehog pathway inhibitors. J Clin Oncol. 28:5321–5326. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Gailani MR and Bale AE: Developmental genes and cancer: Role of patched in basal cell carcinoma of the skin. J Natl Cancer Inst. 89:1103–1109. 1997. View Article : Google Scholar : PubMed/NCBI

9 

Zurawel RH, Allen C, Chiappa S, Cato W, Biegel J, Cogen P, de Sauvage F and Raffel C: Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma. Genes Chromosomes Cancer. 27:44–51. 2000. View Article : Google Scholar : PubMed/NCBI

10 

Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgård R and Undén AB: Deregulation of the hedgehog signalling pathway: A possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol. 208:17–25. 2006. View Article : Google Scholar : PubMed/NCBI

11 

Kinzler KW, Bigner SH, Binger DD, Trent JM, Law ML, O'Brien SJ, Wong AJ and Vogelstein B: Identification of an amplified, highly expressed gene in a human glioma. Science. 236:70–73. 1987. View Article : Google Scholar : PubMed/NCBI

12 

Thayer SP, di Magliano MP, Heiser PW, Nielson CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Castillo CF, Yajnik V, et al: Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 425:851–856. 2003. View Article : Google Scholar : PubMed/NCBI

13 

Qualtrough D, Buda A, Gaffield W, Williams AC and Paraskeva C: Hedgehog signalling in colorectal tumour cells: Induction of apoptosis with cyclopamine treatment. Int J Cancer. 110:831–837. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Cheng WT, Xu K, Tian DY, Zhang ZG, Liu LJ and Chen Y: Role of Hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells. Int J Oncol. 34:829–836. 2009.PubMed/NCBI

15 

Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA and Baylin SB: Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature. 422:313–317. 2003. View Article : Google Scholar : PubMed/NCBI

16 

Chen X, Horiuchi A, Kikuchi N, Osada R, Yoshida J, Shiozawa T and Konishi I: Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis. Cancer Sci. 98:68–76. 2007. View Article : Google Scholar : PubMed/NCBI

17 

Ma X, Chen K, Huang S, Zhang X, Adegboyega PA, Evers BM, Zhang H and Xie J: Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis. 26:1698–1705. 2005. View Article : Google Scholar : PubMed/NCBI

18 

Fan L, Pepicelli CV and Dibble CC: Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology. 145:3961–3970. 2004. View Article : Google Scholar : PubMed/NCBI

19 

Yamasaki A, Kameda C, Xu R, Tanaka H, Tasaka T, Chikazawa N, Suzuki H, Morisaki T, Kubo M, Onishi H, et al: Nuclear factor kappaB-activated monocytes contribute to pancreatic cancer progression through the production of Shh. Cancer Immunol Immunother. 59:675–686. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Hockel S, Schlenger K, Vaupel P and Hockel M: Association between host tissue vascularity and the prognostically relevant tumor vascularity in human cervical cancer. Int J Oncol. 19:827–832. 2001.PubMed/NCBI

21 

Lei J, Ma J, Ma Q, Li X, Liu H, Xu Q, Duan W, Sun Q, Xu J, Wu Z and Wu E: Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner. Mol Cancer. 12:662013. View Article : Google Scholar : PubMed/NCBI

22 

Onishi H, Yamasaki A, Kawamoto M, Imaizumi A and Katano M: Hypoxia but not normoxia promotes Smoothened transcription through upregulation of RBPJ and Mastermind-like 3 in pancreatic cancer. Cancer Lett. 371:143–150. 2016. View Article : Google Scholar : PubMed/NCBI

23 

Ables JL, Breunig JJ, Eisch AJ and Rakic P: Not(ch) just development: Notch signalling in the adult brain. Nat Rev Neurosci. 12:269–283. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Onishi H, Ichimiya S, Yanai K, Umebayashi M, Nakamura K, Yamasaki A, Imaizumi A, Nagai S, Murahashi M, Ogata H and Morisaki T: RBPJ and MAML3: Potential therapeutic targets for small cell lung cancer. Anticancer Res. 38:4543–4547. 2018. View Article : Google Scholar : PubMed/NCBI

25 

Tai H, Wu Z, Sun S, Zhang Z and Xu C: FGFRL1 promotes ovarian cancer progression by crosstalk with hedgehog signaling. J Immunol Res. 2018:74386082018. View Article : Google Scholar : PubMed/NCBI

26 

Cao Y, Lin SH, Wang Y, Chin YE, Kang L and Mi J: Gultamic pyruvate transaminase GPT2 promotes tumorigenesis of breast cancer cells by activating sonic hedgehog signaling. Theranostics. 7:3021–3033. 2017. View Article : Google Scholar : PubMed/NCBI

27 

Xu QH, Xiao Y, Li XQ, Fan L, Zhou CC, Cheng L, Jiang ZD and Wang GH: Resveratrol counteracts hypoxia-induced gastric cancer invasion and EMT through hedgehog pathway suppression. Anticancer Agents Med Chem. 20:1105–1114. 2020. View Article : Google Scholar : PubMed/NCBI

28 

Wei M, Ma R, Huang S, Liao Y, Ding Y, Li Z, Guo Q, Tan R, Zhang L and Zhao L: Oroxylin A increases the sensitivity of temozolomide on glioma cells by hypoxia-inducible factor 1α/hedgehog pathway under hypoxia xia. J Cell Physiol. 234:17392–17404. 2019. View Article : Google Scholar : PubMed/NCBI

29 

Sarighieh MA, Montazeri V, Shadboorestan A, Ghahremani MH and Ostad SN: The inhibitory effect on hypoxia inducer (Hifs) as a regulatory factor in the growth of tumor cells in breast cancer stem-like cells. Drug Res. 70:512–518. 2020. View Article : Google Scholar : PubMed/NCBI

30 

Cao L, Xiao X, Lei J, Duan W, Ma Q and Li W: Curcumin inhibits hypoxia-induced epithelial-mesenchymal transition in pancreatic cancer cells via suppression of the hedgehog signaling pathway. Oncol Rep. 35:3728–3734. 2016. View Article : Google Scholar : PubMed/NCBI

31 

Fu Z, Chen D, Cheng H and Wang F: Hypoxia-inducible factor-1α protects cervical carcinoma cells from apoptosis induced by radiation via modulation of vascular endothelial growth factor and p53 under hypoxia. Med Sci Monit. 21:319–325. 2015.

32 

Meng X, Cai J, Liu J, Han B, Gao F, Gao W, Zhang Y, Zhang J, Zhao Z and Jiang C: Curcumin increases efficiency of γ-irradiation in gliomas by inhibiting Hedgehog signaling pathway. Cell Cycle. 16:1181–1192. 2017. View Article : Google Scholar : PubMed/NCBI

33 

Zhang F, Hao M, Jin H, Yao Z, Lian N, Wu L, Shao J, Chen A and Zheng S: Canonical hedgehog signalling regulates hepatic stellate cell-mediated angiogenesis in liver fibrosis. Br J Pharmacol. 175:409–423. 2017. View Article : Google Scholar

34 

Zhang Q, Lou Y, Zhang J, Fu Q, Wei T, Sun X, Chen Q, Yang J, Bai X and Liang T: Hypoxia-inducible factor-2α promotes tumor progression and has crosstalk with Wnt/β-catenin signaling in pancreatic cancer. Mol Cancer. 16:1192017. View Article : Google Scholar : PubMed/NCBI

35 

Criscimanna A, Duan LJ, Rhodes JA, Fendrich V, Wickline E, Hartman DJ, Monga SP, Lotze MT, Gittes GK, Fong GH and Esni F: PanIN-specific regulation of Wnt signaling by HIF2α during early pancreatic tumorigenesis. Cancer Res. 73:4781–4790. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Moriyama H, Moriyama M, Ozawa T, Ttsuruta D, Iguchi T, Tamada S, Nakatani T, Nakagawa K and Hayakawa T: Notch signaling enhances stemness by regulating metabolic pathways through modifying p53, NF-κB, and HIF-1α. Stem Cells Dev. 27:935–947. 2018. View Article : Google Scholar : PubMed/NCBI

37 

Tian Q, Xue Y, Zheng W, Sun R, Ji W, Wang X and An R: Overexpression of hypoxia-inducible factor 1α induces migration and invasion through Notch signaling. Int J Oncol. 47:728–738. 2015. View Article : Google Scholar : PubMed/NCBI

38 

Kroon ME, Koolwijk P, van der Vecht B and van Hinsbergh VW: Hypoxia in combination with FGF-2 induces tube formation by human microvascular endothelial cells in a fibrin matrix: Involvement of at least two signal transduction pathways. J Cell Sci. 114:825–833. 2001. View Article : Google Scholar : PubMed/NCBI

39 

Le TBU, Vu TC, Ho RZW, Prawira A, Wang L, Goh BC and Huynh H: Bevacizumab augments the antitumor efficacy of infigratinib in hepatocellular carcinoma. Int J Mol Sci. 21:94052020. View Article : Google Scholar : PubMed/NCBI

40 

Gupta SC, Singh R, Pochampally R, Watabe K and Mo YY: Acidosis promotes invasiveness of vreast cancer cells through ROS-AKT-NF-kB pathway. Oncotarget. 5:12070–12082. 2014. View Article : Google Scholar : PubMed/NCBI

41 

Prasad S, Gupta SC and Tyagi AK: Reactive oxygen species (ROS) and cancer: Role of antioxidative nutraceuticals. Cancer Lett. 387:95–105. 2017. View Article : Google Scholar : PubMed/NCBI

42 

Eyrich NW, Potts CR, Robinson MH, Maximov V and Kenney AM: Reactive oxygen species signaling promotes hypoxia-inducible factor 1 α stabilization in sonic hedgehog-driven cerebellar progenitor cell proliferation. Mol Cell Biol. 39:e00268–18. 2019. View Article : Google Scholar : PubMed/NCBI

43 

Liu Z, Tu K, Wang Y, Yao B, Li Q, Wang L, Dou C, Liu Q and Zheng X: Hypoxia accelerates aggressiveness of hepatocellular carcinoma cells involving oxidative stress, epithelial-mesenchymal transition and non-canonical hedgehog signaling. Cell Physiol Biochem. 44:1856–1868. 2017. View Article : Google Scholar : PubMed/NCBI

44 

Li W, Cao L, Chen Y, Lei J and Ma Q: Resveratrol inhibits hypoxia-driven ROS-induced invasive and migratory ability of pancreatic cancer cells via suppression of the hedgehog signaling pathway. Oncol Rep. 35:1718–1726. 2016. View Article : Google Scholar : PubMed/NCBI

45 

Morifuji Y, Onishi H, Iwasaki H, Imaizumi A, Nakano K, Tanaka M and Katano M: Reoxygenation from chronic hypoxia promotes metastatic processes in pancreatic cancer through the Hedgehog signaling. Cancer Sci. 105:324–333. 2014. View Article : Google Scholar : PubMed/NCBI

46 

Zhang RY, Qiao ZY, Liu HJ and Ma JW: Sonic hedgehog signaling regulates hypoxia/reoxygenation-induced H9C2 myocardial cell apoptosis. Exp Ther Med. 16:4193–4200. 2018.PubMed/NCBI

47 

Fang Q, Zhang Y, Siang DS and Chen Y: Hydroxytyosol inhibits apoptosis in ischemia/reperfusion-induced acute kidney injury via activating sonic edgehog signaling pathway. Eur Rev Med Pharmacol Sci. 24:12380–12388. 2020.PubMed/NCBI

48 

Emami Nejad A, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M, Nedaeinia R, Haghjooy Javanmard S, Taherian M, Ahmadlou M, et al: The role of hypoxia in the tumor microenvironment and development of cancer stem cell: A novel approach to developing treatment. Cancer Cell Int. 21:622021. View Article : Google Scholar : PubMed/NCBI

49 

Chapouly C, Guimbal S, Hollier PL and Renault MA: Role of hedgehog signaling in vasculature development, differentiation, and maintenance. Int J Mol Sci. 20:30762019. View Article : Google Scholar : PubMed/NCBI

50 

Yang X, Wang Z, Kai J, Wang F, Jia Y, Wang S, Tan S, Shen X, Chen A, Shao J, et al: Curcumol attenuates liver sinusoidal endothelial cell angiogenesis via regulating Glis-PROX1-HIF-1 α in liver fibrosis. Cell Prolif. 53:e127622020. View Article : Google Scholar : PubMed/NCBI

51 

Pinter M, Sieghart W, Schmid M, Dauser B, Prager G, Dienes HP, Trauner M and Peck-Radosavljevic M: Hedgehog inhibition reduces angiogenesis by downregulation of tumoral VEGF-A expression in hepatocellular carcinoma. United European Gastroenterol J. 1:265–275. 2013. View Article : Google Scholar : PubMed/NCBI

52 

Zhu XQ, Yang H, Lin MH, Shang HX, Peng J, Chen WJ, Chen XZ and Lin JM: Qingjie fuzheng granules regulates cancer cell proliferation, apoptosis and tumor angiogenesis in colorectal cancer xenograft mice via sonic hedgehog pathway. J Gastrointest Oncl. 11:1123–1134. 2020. View Article : Google Scholar : PubMed/NCBI

53 

Zhu ZX, Sun CC, Zhu YT, Wang Y, Wang T, Chi LS, Cai WH, Zheng JY, Zhou X, Cong WT, et al: Hedgehog signaling contributes to basic fibroblast growth factor-regulated fibroblast migration. Exp Cell Res. 355:83–94. 2017. View Article : Google Scholar : PubMed/NCBI

54 

Yao Q, Renault MA, Chapouly C, Vandierdonck S, Belloc I, Jaspard-Vinassa B, Daniel-Lamaziere JM, Laffargue M, Merched A, Desgranges C and Gadeau AP: Sonic hedgehog mediates a novel pathway of PDGF-BB-dependent vessel maturation. Blood. 123:2529–2437. 2014. View Article : Google Scholar

55 

Hsieh A, Ellsworth R and Hsieh D: Hedgehog/GLI1 regulates IGF dependent malignant behaviors in glioma stem cells. J Cell Physiol. 226:1118–1127. 2011. View Article : Google Scholar : PubMed/NCBI

56 

Maroufy V, Shah P, Asghari A, Deng N, Le RNU, Ramirez JC, Yaseen A, Zheng WJ, Umetami M and Wu H: Gene expression dynamic analysis reveals co-activation of sonic hedgehog and epidermal growth factor followed by dynamic silencing. Oncotarget. 11:1358–1372. 2020. View Article : Google Scholar : PubMed/NCBI

57 

Bausch D, Fritz S, Bolm L, Wellner UF, Fernandez-Del-Castillo C, Warshaw AL, Thayer SP and Liss AS: Hedgehog signaling promotes angiogenesis directly and indirectly in pancreatic cancer. Angiogenesis. 23:479–492. 2020. View Article : Google Scholar : PubMed/NCBI

58 

Stewart GA, Hoyne GF, Ahmad SA, Jarman E, Wallace WAH, Harrison DJ, Haslett C, Lamb JR and Howie SEM: Expression of the developmental sonic hedgehog (Shh) signalling pathway is up-regulated in chronic lung fibrosis and the Shh receptor patched 1 is present in circulating T lymphocytes. J Pathol. 199:488–495. 2003. View Article : Google Scholar : PubMed/NCBI

59 

Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, Witek RP, Alpini G, Venter J, Vandongen HM, et al: Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest. 118:3331–3342. 2008.PubMed/NCBI

60 

Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, Caffery TC, Ouellette MM and Hollingsworth MA: Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res. 14:5995–6004. 2008. View Article : Google Scholar : PubMed/NCBI

61 

Spivak-Kroizman TR, Hostetter G, Posner R, Ariz M, Hu C, Demeure MJ, Hoff DV, Hingorani SR, Palculict TB, Izzo J, et al: Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer. Cancer Res. 73:3235–3247. 2013. View Article : Google Scholar : PubMed/NCBI

62 

Katagiri T, Kobayashi M, Yoshimura M, Morinibu A, Itasaka S, Hiraoka M and Harada H: HIF-1 maintains a functional relationship between pancreatic cancer cells and stromal fibroblasts by upregulating expression and secretion of sonic hedgehog. Oncotarget. 9:10525–10535. 2018. View Article : Google Scholar : PubMed/NCBI

63 

Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, et al: Inhibition of hedgehog signaling enhances delivery of chemotherapy in mouse model of pancreatic cancer. Science. 324:1457–1461. 2009. View Article : Google Scholar : PubMed/NCBI

64 

Oyama Y, Onishi H, Koga S, Murahashi M, Ichimiya S, Nakayama K, Fujimura A, Kawamoto M, Imaizumi A, Umebayashi M, et al: Patched 1-interacting peptide represses fibrosis in pancreatic cancer to augment the effectiveness of immunotherapy. J Immunother. 43:121–133. 2020. View Article : Google Scholar : PubMed/NCBI

65 

Steele NG, Biffi G, Kemp SB, Zhang Y, Drouillard D, Syu L, Hao Y, Oni TE, Brosnan E, Elyada E, et al: Inhibition of hedgehog signaling alters fibroblast composition in pancreatic cancer. Clin Cancer Res. 27:2023–2037. 2021. View Article : Google Scholar : PubMed/NCBI

66 

Xue J, Jsharma V, Hsieh MH, Chawla A, Murali R, Pandol SJ and Habtezion A: Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis. Nat Commun. 6:71582015. View Article : Google Scholar : PubMed/NCBI

67 

Ueshima E, Fujimori M, Kodama H, Felsen D, Chen J, Duack JC, Solomon SB, Coleman JA and Srimathveeravalli G: Macrophage-secreted TGF-β 1 contributes to fibroblast activation and ureteral stricture after ablation injury. Am J Physiol Renol Physiol. 317:F52–F64. 2019. View Article : Google Scholar : PubMed/NCBI

68 

Javelaud D, Pierrat MJ and Mauviel A: Crosstalk between TGF-β and hedgehog signaling in cancer. FEBS Lett. 586:2016–2025. 2012. View Article : Google Scholar : PubMed/NCBI

69 

Dennler S, Andre J, Alexaki I, Li A, Magnaldo T, ten Dijke P, Wang XJ, Verrecchia F and Mauviel A: Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res. 67:6981–6986. 2007. View Article : Google Scholar : PubMed/NCBI

70 

Zhou X, Wang P, Ma Z, Li M, Teng X, Sun L, Wan G, Li Y, Guo L and Liu H: Novel interplay between sonic hedgehog and transforming growth factor-β1 in human nonalcoholic steatohepatitis. Appl Immunohistochem Mol Morphol. 28:154–160. 2020. View Article : Google Scholar : PubMed/NCBI

71 

Jiayuan S, Junyan Y, Xiangzhen W, Zuping W, Jian N, Baowei H and Lifang J: Gant61 ameliorates CCl4-induced liver fibrosis by inhibition of hedgehog signaling activity. Toxicol Appl Pharmcol. 387:1148532020. View Article : Google Scholar : PubMed/NCBI

72 

Noman MZ, Hasmim M, Messai Y, Terry S, Kieda C, Janji B and Chouaib S: Hypoxia: A key player in antitumor immune response. A review in the theme: Cellular responses to hypoxia. Am J Physiol Cell Physiol. 309:C569–C579. 2015. View Article : Google Scholar : PubMed/NCBI

73 

Onishi H, Morisaki T, Kiyota A, Koya N, Tanaka H, Umebayashi M and Katano M: The Hedgehog inhibitor cyclopamine impairs the benefits of immunotherapy with activated T and NK lymphocytes derived from patients with advanced cancer. Cancer Immunol Immunother. 62:1029–1039. 2013. View Article : Google Scholar : PubMed/NCBI

74 

Winning S and Fandrey J: Dendritic cells under hypoxia: How oxygen shortage affects the linkage between innate and adaptive immunity. J Immunol Res. 2016:51343292016. View Article : Google Scholar : PubMed/NCBI

75 

Ogino T, Onishi H, Suzuki H, Morisaki T, Tanaka M and Katano M: Inclusive estimation of complex antigen presentation functions of monocyte-derived dendritic cells differentiated under normoxia and hypoxia conditions. Cancer Immunol Immunother. 61:409–424. 2012. View Article : Google Scholar : PubMed/NCBI

76 

Bosco MC, Pierobon D, Blengio F, Raggi F, Vanni C, Gattorno M, Eva A, Novelli F, Cappello P, Giovarelli M and Varesio L: Hypoxia modulates the gene expression profile of immunoregulatory receptors in human mature dendritic cells: Identification of TREM-1 as a novel hypoxic marker in vitro and in vivo. Blood. 117:2625–2639. 2011. View Article : Google Scholar : PubMed/NCBI

77 

Pierobon D, Bosco MC, Blengio F, Raggi F, Eva A, Filippi M, Musso T, Novelli F, Cappello P, Varesio L and Giovarelli M: Chronic hypoxia reprograms human immature dendritic cells by inducing a proinflammatory phenotype and TREM-1 expression. Eur J Immunol. 43:949–966. 2013. View Article : Google Scholar : PubMed/NCBI

78 

Liu B and Wei C: Hypoxia induces overexpression of CCL28 to recruit Treg cells to enhance angiogenesis in lung adenocarcinoma. J Environ Pathol Toxicol Oncol. 40:65–74. 2021. View Article : Google Scholar : PubMed/NCBI

79 

Westendorf AM, Skibbe K, Adamczyk A, Buer J, Geffers R, Hansen W, Pastille E and Jendrossek V: Hypoxia enhances immunosuppression by inhibiting CD4+ Effector T cell function and promoting treg activity. Cell Physiol Biochem. 41:1271–1284. 2017. View Article : Google Scholar : PubMed/NCBI

80 

Chiu DK, Xu IM, Lai RK, Tse AP, Wei LL, Koh HY, Li LL, Lee D, Lo RC, Wong CM, et al: Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26. Hepatology. 64:797–813. 2016. View Article : Google Scholar : PubMed/NCBI

81 

Elia AR, Cappello P, Puppo M, Fraone T, Vanni C, Eva A, Musso T, Novelli F, Varesio L and Giovarelli M: Human dendritic cells differentiated in hypoxia down-modulate antigen uptake and change their chemokine expression profile. J Leukoc Biol. 84:1472–1482. 2008. View Article : Google Scholar : PubMed/NCBI

82 

Burke B, Giannoudis A, Corke KP, Gill D, Wells M, Ziegler-Heitbrock L and Lewis CE: Hypoxia-induced gene expression in human macrophages: Implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol. 163:1233–1243. 2003. View Article : Google Scholar : PubMed/NCBI

83 

Fingleton B, Vargo-Gogola T, Crawford HC and Matrisian LM: Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis. Neoplasia. 3:459–468. 2001. View Article : Google Scholar : PubMed/NCBI

84 

Sureshbabu SK, Chaukar D and Chiplunkar SV: Hypoxia regulates the differentiation and anti-tumor effector functions of γδT cells in oral cancer. Clin Exp Immunol. 201:40–57. 2020. View Article : Google Scholar : PubMed/NCBI

85 

de la Roche M, Ritter AT, Angus KL, Dinsmore C, Earnshaw CH, Reiter JF and Griffiths GM: Hedgehog signaling controls T cell killing at the immunological synapse. Science. 342:1247–1250. 2013. View Article : Google Scholar : PubMed/NCBI

86 

Petty AJ, Li A, Wang X, Dai R, Heyman B, Hsu D, Huang X and Yang YJ: Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment. Clin Invest. 129:5151–5162. 2019. View Article : Google Scholar : PubMed/NCBI

87 

Yánez DC, Lau CI, Chawda MM, Ross S, Furmanski AL and Crompton TJ: Hedgehog signaling promotes T H 2 differentiation in naive human CD4 T cells. Allergy Clin Immunol. 144:1419–1423.e1. 2019. View Article : Google Scholar : PubMed/NCBI

88 

Merchant JL and Ding L: Hedgehog signaling links chronic inflammation to gastric cancer precursor lesions. Cell Mol Gastroenterol Hepatol. 3:201–210. 2017. View Article : Google Scholar : PubMed/NCBI

89 

Onishi H, Morisaki T, Kiyota A, Koya N, Tanaka H, Umebayashi M and Katano M: The Hedgehog inhibitor suppresses the function of monocyte-derived dendritic cells from patients with advanced cancer under hypoxia. Biochem Biophys Res Commun. 436:53–59. 2013. View Article : Google Scholar : PubMed/NCBI

90 

Ichimiya S, Fujimura A, Masuda M, Masuda S, Yasumatsu R, Umebayashi M, Tanaka H, Koya N, Nakagawa S, Yoshimura S, Onishi H, Nakamura M, Nakamura Y and Morisaki T: Contribution of pre-existing neoantigen-specific T cells to durable complete responses after tumor-pulsed dendritic cell vaccine plus nivolumab therapy in a patient with metastatic salivary duct carcinoma. Immunol Invest. Sep 5–2021.(Epub ahead of print). doi: 10.1080/08820139.2021.1973491. View Article : Google Scholar : PubMed/NCBI

91 

Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, Bronte V and Chouaib S: PD-L1 is a novel direct target of HIF-1α, and its blockade under ypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 211:781–790. 2014. View Article : Google Scholar : PubMed/NCBI

92 

Cubillos-Zapata C, Avendaño-Ortiz J, Hernandez-Jimenez E, Toledano V, Casas-Martin J, Varela-Serrano A, Torres M, Almendros I, Casitas R, Fernández-Navarro I, et al: Hypoxia-induced PD-L1/PD-1 crosstalk impairs T-cell function in sleep apnoea. Eur Respir J. 50:17008332017. View Article : Google Scholar : PubMed/NCBI

93 

Chakrabarti J, Holokai L, Syu L, Steele NG, Chang J, Wang J, Ahmed S, Dlugosz A and Zavros Y: Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer. Oncotarget. 9:37439–37457. 2018. View Article : Google Scholar : PubMed/NCBI

94 

Onishi H, Fujimura A, Oyama Y, Yamasaki A, Imaizumi A, Kawamoto M, Katano M, Umebayashi M and Morisaki T: Hedgehog signaling regulates PDL-1 expression in cancer cells to induce anti-tumor activity by activated lymphocytes. Cell Immunol. 310:199–204. 2016. View Article : Google Scholar : PubMed/NCBI

95 

Zhu X and Lang J: Soluble PD-1 and PD-L1: Predictive and prognostic significance in cancer. Oncotarget. 8:97671–97682. 2017. View Article : Google Scholar : PubMed/NCBI

96 

Zhou K, Guo S, Li F, Sun Q and Liang G: Exosomal PD-L1: New insights into tumor immune escape mechanisms and therapeutic strategies. Front Cell Dev Biol. 8:5692192020. View Article : Google Scholar : PubMed/NCBI

97 

Mühlbauer M, Fleck M, Schütz C, Weiss T, Froh M, Blank C, Schölmerich J and Hellerbrand C: PD-L1 is induced hepatocytes by viral infection and interferon-alpha and -gamma and mediates T cell apoptosis. J Hepatol. 45:520–528. 2006. View Article : Google Scholar : PubMed/NCBI

98 

D'Alessandris N, Palaia I, Pernazza A, Tomao F, Di Pinto A, Musacchio L, Leopizzi M, Di Maio V, Pecorella I, Benedetti Panici P, et al: PD-L1 expression is associated with tumor infiltrating lymphocytes that predict response to NACT in squamous cell cervical cancer. Virchows Arch. 478:517–525. 2021. View Article : Google Scholar : PubMed/NCBI

99 

Blank C and Mackensen A: Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: An update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother. 56:739–745. 2007. View Article : Google Scholar : PubMed/NCBI

100 

Zeng X and Ju D: Hedgehog signaling pathway and autophagy in cancer. Int J Mol Sci. 19:22792018. View Article : Google Scholar : PubMed/NCBI

101 

Yamasaki A, Yanai K and Onishi H: Hypoxia and pancreatic ductal adenocarcinoma. Cancer Lett. 484:9–15. 2020. View Article : Google Scholar : PubMed/NCBI

102 

Milla LA, González-Ramírez CN and Palma V: Sonic hedgehog in cancer stem cells: A novel link with autophagy. Biol Res. 45:223–230. 2012. View Article : Google Scholar : PubMed/NCBI

103 

Wu X, Won H and Rubinsztein DC: Autophagy and mammalian development. Biochem Soc Trans. 41:1489–1494. 2013. View Article : Google Scholar : PubMed/NCBI

104 

Fan J, Ju D, Li Y, Wang S and Wang Z: A novel approach to overcome non-small-cell lung cancer: Co-inhibition of autophagy and Hedgehog pathway. Ann Oncol. 26:vii106–vii151. 2015. View Article : Google Scholar

105 

Wang Y, Han C, Lu L, Magliato S and Wu T: Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology. 58:995–1010. 2013. View Article : Google Scholar : PubMed/NCBI

106 

Gagné-Sansfaçon J, Allaire JM, Jones C, Boudreau F and Perreault N: Loss of Sonic hedgehog leads to alterations in intestinal secretory cell maturation and autophagy. PLoS One. 9:e987512014. View Article : Google Scholar : PubMed/NCBI

107 

Albini A, Cesana E and Noonan DM: Cancer stem cells and the tumor microenvironment: Soloists or choral singers. Curr Pharm Biotechnol. 12:171–181. 2011. View Article : Google Scholar : PubMed/NCBI

108 

Wu CP, Du HD, Gong HL, Li DW, Tao L, Tian J and Zhou L: Hypoxia promotes stem-like properties of laryngeal cancer cell lines by increasing the CD133+ stem cell fraction. Int J Oncol. 44:1652–1660. 2014. View Article : Google Scholar : PubMed/NCBI

109 

Sun X, Lv X, Yan Y, Zhao Y, Ma R, He M and Wei M: Hypoxia-mediated cancer stem cell resistance and targeted therapy. Biomed. Pharmacother. 130:1106232020. View Article : Google Scholar : PubMed/NCBI

110 

Bhuria V, Xing J, Scholta T, Bui KC, Nguyen MLT, Malek NP, Bozko P and Plentz RR: Hypoxia induced Sonic Hedgehog signaling regulates cancer stemness, epithelial-to-mesenchymal transition and invasion in cholangiocarcinoma. Exp Cell Res. 385:1116712019. View Article : Google Scholar : PubMed/NCBI

111 

Raghavan S, Snyder CS, Wang A, McLean K, Zamarin D, Buckanovich RJ and Mehta G: Carcinoma-associated mesenchymal stem cells promote chemoresistance in ovarian cancer stem cells via PDGF signaling. Cancers. 12:20632020. View Article : Google Scholar : PubMed/NCBI

112 

Mondal S, Bhattacharya K and Mandal C: Nutritional stress reprograms dedifferention in glioblastoma multiforme driven by PTEN/Wnt/Hedgehog axis: A stochastic model of cancer stem cells. Cell Death Discov. 4:1102018. View Article : Google Scholar : PubMed/NCBI

113 

Tanaka H, Nakamura M, Kameda C, Kubo M, Sato N, Kuroki S, Tanaka M and Katano M: The Hedgehog signaling pathway plays an essential role in maintaining the CD44+CD24-/low subpopulation and the side population of breast cancer cells. Anticancer Res. 29:2147–2157. 2009.PubMed/NCBI

114 

Bai JW, Wei M, Li JW and Zhang GJ: Notch signaling pathway and endocrine resistance in breast cancer. Front Pharmacol. 11:9242020. View Article : Google Scholar : PubMed/NCBI

115 

Shang C, Lang B and Meng LR: Blocking NOTCH pathway can enhance the effect of EGFR inhibitor through targeting CD133+ endometrial cancer cells. Cancer Biol Ther. 19:113–119. 2018. View Article : Google Scholar : PubMed/NCBI

116 

Castagnoli L, Tagliabue E and Pupa SM: Inhibition of the Wnt signalling pathway: An avenue to control breast cancer aggressiveness. Int J Mol Sci. 21:90692020. View Article : Google Scholar : PubMed/NCBI

117 

Pandit H, Li Y, Li X, Zhang W, Li S and Martin RCG: Enrichment of cancer stem cells via β-catenin contributing to the tumorigenesis of hepatocellular carcinoma. BMC Cancer. 18:7832018. View Article : Google Scholar : PubMed/NCBI

118 

Gargiulo G, Cesaroni M, Serresi M, de Vries N, Hulsman D, Bruggeman SW, Lancini C and van Lohuizen M: In vivo RNAi screen for BMI1 targets identifies TGF-β/BMP-ER stress pathways as key regulators of neural- and malignant glioma-stem cell homeostasis. Cancer Cell. 23:660–676. 2013. View Article : Google Scholar : PubMed/NCBI

119 

Ader T, Norel R, Levoci L and Rogler LE: Transcriptional profiling implicates TGFbeta/BMP and Notch signaling pathways in ductular differentiation of fetal murine hepatoblasts. Mech Dev. 123:177–194. 2006. View Article : Google Scholar : PubMed/NCBI

120 

Schartz NE, Chaput N, André F and Zitvogel L: From the antigen-presenting cell to the antigen-presenting vesicle: The exosomes. Curr Opin Mol Ther. 4:372–381. 2002.PubMed/NCBI

121 

Mignot G, Roux S, Thery C, Segura E and Zitvogel L: Prospects for exosomes in immunotherapy of cancer. J Cell Mol Med. 10:376–388. 2006. View Article : Google Scholar : PubMed/NCBI

122 

Deep G and Panigrahi GK: Hypoxia-induced signaling promotes prostate cancer progression: Exosomes role as messenger of hypoxic response in tumor microenvironment. Crit Rev Oncog. 20:419–434. 2015. View Article : Google Scholar : PubMed/NCBI

123 

Gradilla AC, González E, Seijo I, Andrés G, Bischoff M, González-Mendez L, Sánchez V, Callejo A, Ibáñez C, Guerra M, et al: Exosomes as Hedgehog carriers in cytoneme-mediated transport and secretion. Nat Commun. 5:56492014. View Article : Google Scholar : PubMed/NCBI

124 

Qi J, Zhou Y, Jiao Z, Wang X, Zhao Y and Li Y, Chen H, Yang L, Zhu H and Li Y: Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth through hedgehog signaling pathway. Cell Physiol Biochem. 42:2242–2254. 2017. View Article : Google Scholar : PubMed/NCBI

125 

Sharma A: Role of stem cell derived exosomes in tumor biology. Int J Cancer. 142:1086–1092. 2018. View Article : Google Scholar : PubMed/NCBI

126 

Bhat A, Sharma A and Bharti AC: Upstream Hedgehog signaling components are exported in exosomes of cervical cancer cell lines. Nanomedicine. 13:2127–2138. 2018. View Article : Google Scholar : PubMed/NCBI

127 

Zhao G, Li H, Guo Q, Zhou A, Wang X, Li P and Zhang S: Exosomal Sonic Hedgehog derived from cancer-associated fibroblasts promotes proliferation and migration of esophageal squamous cell carcinoma. Cancer Med. 9:2500–2513. 2020. View Article : Google Scholar : PubMed/NCBI

128 

Wada J, Onishi H, Suzuki H, Yamasaki A, Nagai S, Morisaki T and Katano M: Surface-bound TGF-beta1 on effusion-derived exosomes participates in maintenance of number and suppressive function of regulatory T-cells in malignant effusions. Anticancer Res. 30:3747–3757. 2010.PubMed/NCBI

129 

Matsumoto K, Morisaki T, Kuroki H, Kubo M, Onishi H, Nakamura K, Nakahara C, Kuga H, Baba E, Nakamura M, et al: Exosomes secreted from monocyte-derived dendritic cells support in vitro naïve CD4+ T cell survival through NF-(kappa)B activation. Cell Immunol. 231:20–29. 2004. View Article : Google Scholar : PubMed/NCBI

130 

Onishi H, Kuroki H, Matsumoto K, Baba E, Sasaki N, Kuga H, Tanaka M, Katano M and Morisaki T: Monocyte-derived dendritic cells that capture dead tumor cells secrete IL-12 and TNF-alpha through IL-12/TNF-alpha/NF-kappaB autocrine loop. Cancer Immunol Immunother. 53:1093–1100. 2004. View Article : Google Scholar : PubMed/NCBI

131 

Nakashima H, Nakamura M, Yamaguchi H, Yamanaka N, Akiyoshi T, Koga K, Yamaguchi K, Tsuneyoshi M, Tanaka M and Katano M: Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. Cancer Res. 66:7041–7049. 2006. View Article : Google Scholar : PubMed/NCBI

132 

Kasperczyk H, Baumann B, Debatin KM and Fulda S: Characterization of sonic hedgehog as a novel NF-kappaB target gene that promotes NF-kappaB-mediated apoptosis resistance and tumor growth in vivo. FASEB J. 23:21–33. 2009. View Article : Google Scholar : PubMed/NCBI

133 

Cai K, Na W, Guo M, Xu R, Wang X, Qin Y, Wu Y, Jiang J and Huang H: Targeting the cross-talk between the hedgehog and NF-κB signaling pathways in multiple myeloma. Leuk Lymphoma. 60:772–781. 2019. View Article : Google Scholar : PubMed/NCBI

134 

Nakayama K, Onishi H, Fujimura A, Imaizumi A, Kawamoto M, Oyama Y, Ichimiya S, Koga S, Fujimoto Y, Nakashima K and Nakamura M: NFκB and TGFβ contribute to the expression of PTPN3 in activated human lymphocytes. Cell Immunol. 358:1042372020. View Article : Google Scholar : PubMed/NCBI

135 

Fosko SW, Chu MB, Armbrecht E, Galperin T, Potts GA, Mattox A, Kurta A, Polito K, Slutsky JB, Burkemper NM, et al: Efficacy, rate of tumor response, and safety of a short course (12–24 weeks) of oral vismodegib in various histologic subtypes (infiltrative, nodular, and superficial) of high-risk or locally advanced basal cell carcinoma, in an open-label, prospective case series clinical trial. J Am Acad Dermatol. 82:946–954. 2020. View Article : Google Scholar : PubMed/NCBI

136 

De Jesus-Acosta A, Sugar EA, O'Dwyer PJ, Ramanathan RK, Von Hoff DD, Rasheed Z, Zheng L, Begum A, Anders R, Maitra A, et al: Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma. Br J Cancer. 122:498–505. 2020. View Article : Google Scholar : PubMed/NCBI

137 

Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, et al: Smoothened mutation confere resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 326:572–574. 2009. View Article : Google Scholar : PubMed/NCBI

138 

Dijkgraaf GJ, Alicke B, Weinmann L, Januario T, West K, Modrusan Z, Burdick D, Goldsmith R, Robarge K, Sutherlin D, et al: Small molecule inhibition of GDC-0499 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 71:435–444. 2011. View Article : Google Scholar : PubMed/NCBI

139 

Onishi H and Katano M: The Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer. World J Gastroenterol. 20:2335–2342. 2014. View Article : Google Scholar : PubMed/NCBI

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May-2022
Volume 47 Issue 5

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Copy and paste a formatted citation
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Spandidos Publications style
Onishi H, Nakamura K, Yanai K, Nagai S, Nakayama K, Oyama Y, Fujimura A, Ozono K and Yamasaki A: Cancer therapy that targets the Hedgehog signaling pathway considering the cancer microenvironment (Review). Oncol Rep 47: 93, 2022
APA
Onishi, H., Nakamura, K., Yanai, K., Nagai, S., Nakayama, K., Oyama, Y. ... Yamasaki, A. (2022). Cancer therapy that targets the Hedgehog signaling pathway considering the cancer microenvironment (Review). Oncology Reports, 47, 93. https://doi.org/10.3892/or.2022.8304
MLA
Onishi, H., Nakamura, K., Yanai, K., Nagai, S., Nakayama, K., Oyama, Y., Fujimura, A., Ozono, K., Yamasaki, A."Cancer therapy that targets the Hedgehog signaling pathway considering the cancer microenvironment (Review)". Oncology Reports 47.5 (2022): 93.
Chicago
Onishi, H., Nakamura, K., Yanai, K., Nagai, S., Nakayama, K., Oyama, Y., Fujimura, A., Ozono, K., Yamasaki, A."Cancer therapy that targets the Hedgehog signaling pathway considering the cancer microenvironment (Review)". Oncology Reports 47, no. 5 (2022): 93. https://doi.org/10.3892/or.2022.8304