Xiaotan Sanjie decoction normalizes tumor permissive microenvironment in gastric cancer (Review)
- Authors:
- Published online on: February 28, 2023 https://doi.org/10.3892/or.2023.8511
- Article Number: 74
Abstract
Introduction
Gastric cancer (GC) is one of the most common cancer type in China, and newly diagnosed cases increased from 403,000 in 2015 to 479,000 in 2020 (1). It remains the fourth leading cause of cancer mortality worldwide (2). A large portion of patients with GC do not respond to conventional therapies or are at a higher risk for recurrent disease after they received those interventions, such as perioperative chemotherapy or chemotherapy alone (3,4) and anti-HER2 agent trastuzumab in combination with chemotherapy (5).
Over the last decade, the tumor microenvironment (TME) has become a hot topic for overcoming treatment failure or resistance to current therapies for advanced cancer, including GC (6–8). Various studies have evidenced promising outcomes in patients with GC through targeting angiogenesis, immune suppression and normalization of the tumor-permissive environment (9–15). The Xiaotan Sanjie decoction, a traditional Chinese medicine (TCM) regimen, is composed of 11 traditional medicinal components (16), formulated according to the phlegm syndrome theory (17). Phlegm syndrome, a TCM term, is used to diagnose patients with diseases caused by phlegm (harmful products originated from dysfunctional body fluid circulation) characterized by symptoms and signs including lack of appetite, nausea, vomiting, feel of heavy body, oily looking skin on the face and a pale tongue (18,19). Phlegm syndrome is prevalent in patients with GC (17). Previous preclinical studies have shown that the Xiaotan Sanjie decoction has the ability to regulate levels of some cytokines, growth factors and receptors, such as interleukin-8 (IL-8) (20), transforming growth factor-β (TGF-β) (21), TGF-β receptor 2 (TGFBR2) (22) and CD44V6 (23) in the TME of GC. The Xiaotan Sanjie decoction shows favorable antitumor activities (24) and clinical outcomes (25) in patients with GC.
The TME may constitute the biological basis of phlegm syndrome in patients with GC. We hypothesized that TME in GC may redefine the phlegm syndrome by way of current biomolecular approaches. A literature review was performed to explore the association between phlegm syndrome and the TME, and what roles treatment with the Xiaotan Sanjie decoction played in the management of patients with GC in regard to target components, including cancer-associated fibroblasts (CAFs), extracellular matrix (ECM) and the erratic tumor vasculature within the TME. A preliminary literature search for the Xiaotan Sanjie decoction and TME related articles was performed on the PubMed (https://pubmed.ncbi.nlm.nih.gov/), ScienceDirect (https://www.sciencedirect.com/), Google Scholar (https://scholar.google.com/) and CNKI (https://www.cnki.net/). The following key search terms and phrases were used in combination or separately: ‘Xiaotan Sanjie’, ‘Jinlongshe’ (hospital prepared formulation of Xiaotan Sanjie decoction), ‘phlegm’, ‘phlegm syndrome’, ‘gastric cancer’, ‘tumor microenvironment’, ‘cancer-associated fibroblasts’, ‘extracellular matrix’, ‘transforming growth factor-β’, ‘tumor vasculature’ and ‘angiogenesis’. This may promote translation of TCM theories into modern molecular landscape.
Phlegm syndrome in patients with GC
For >2,000 years, TCM has established a tradition of interpreting diseases and making therapeutic decisions (26). TCM syndrome (pronounced ‘Zheng’ in Chinese), a TCM term, is a combination of the presentation, pathogenesis, site and development tendency of a disease at a specific stage during its course) is based on the gathering of general manifestations of patients through inspection, hearing, inquiry and taking pulse, which is the essential diagnostic process by which TCM physicians describe signs and symptoms and make a treatment plan (27,28). ‘Phlegm syndrome’ is an important type of ‘syndrome’ in TCM. Zhenheng Zhu, a famous TCM physician from the Yuan dynasty (1,279–1,368 AC), said that 9/10 diseases were caused by phlegm (29). TCM has two general types of phlegm: Internal and external (nasal discharge or sputum from respiratory tract) (30). In TCM it is considered that the internal phlegm will arise when the body's fluid metabolism is disturbed by intrinsic or extrinsic factors, such as qi deficiency, qi stagnation, stagnancy of dampness, climatic factors, emotional changes and improper diet (31). The internal phlegm may accumulate in Zang and Fu viscera to disrupt the normal functions of the organs and systems or circulate via meridians and collaterals to distant organs from its source (30). The characteristics of phlegm syndrome can be observed in numerous disorders, including poor general status, respiratory diseases, gastrointestinal disorders, cardiovascular diseases, overweight, neurological dysfunctions and cancer (31).
Numerous major risk factors can be observed in patients with phlegm syndrome and GC concurrently. Improper dietary behaviors take prominent part in the development of phlegm syndrome and GC, such as excessive consumption of pickled or salted food or roasted and greasy foods (17). Overeating itself is also a cause of phlegm (32). H. pylori infection increases the risk of GC; moreover, salted food consumption may further promote H pylori infection, and jointly participate in the development of GC (33). Aging, obesity and chronic inflammation are all commonly found in patients with phlegm syndrome and in patients with GC (32).
GC is characterized by heterogeneous pathology in regard to anatomical location and histological subtypes (33). GC may be detected in almost all parts of the stomach, especially in the lower region (34). GC cells may move from their original site to distant body parts by way of the blood or lymphatic vessels with advancing stages of the disease in patients with GC (35). A broad range of locations should be noted in the diagnostic process, including the abdominal cavity, liver, supraclavicular lymph node, ovaries and umbilical region and Blumer shelf (a mass in the perirectal pouch) (36). Correspondingly, phlegm syndrome presents as a dynamic evolutionary process similar to GC development (32). Phlegm can also be categorized into substantial and insubstantial. Substantial phlegm is visible and palpable, such as scrofula and nodules in the skin and muscles (29). When accumulating, the phlegm is substantial; when dispersing, the phlegm is insubstantial (32). Phlegm arising in the spleen can easily extend to or accumulate in almost all other parts of the body (31), which is referred to as ‘phlegm evil flowing’ in TCM (32). Phlegm may play an important role in the pathogenesis and metastases of GC. Accumulation of internal phlegm transforms from an insubstantial to a substantial phlegmatic nodule in the stomach, and a phlegmatic nodule may create a vicious phlegmatic environment in which it will release more phlegm to relocate to other parts of the body (32).
Composition of Xiaotan Sanjie decoction and TCM usage
The Xiaotan Sanjie decoction is prepared to relieve symptoms and signs of phlegm syndrome in patients with GC. The Xiaotan Sanjie decoction is mainly composed of Pinelliae rhizome, Arisaematis rhizoma, Scorpio, Scolopendra, baked Endothelium corneum gigeriae galli, prepared Glycyrrhiza uralensis Fisch and other natural products (Table I). Pinelliae rhizoma and Arisaematis rhizoma are the dominant ingredients to dry dampness and resolve phlegm, prevent nausea and vomiting, relieve pain and dissolve lumps and resolve masses. Scorpio, Scolopendra and baked Endothelium corneum gigeriae galli are second principal medicinal components to activate the meridians, relieve pain and eliminate phlegmatic nodules. The prepared Glycyrrhiza uralensis Fisch plays a coordinator role to direct other medicines to the sites where affected by phlegm, to reduce toxicity and to improve flavor (37). All of these natural products work synergistically together to improve overall physical status of the patients with GC, especially in patients with advanced disease (17). TCM usages, active compounds and antitumor effects of each component in the Xiaotan Sanjie decoction are described and summarized in a non-exhaustive list in Table I.
Effects of Xiaotan Sanjie decoction on TME in GC
Malfunctioned vascular structures and ECM create a hostile metabolic and mechanical TME that is characterized by hypoxia, low pH and high interstitial pressure (38). Tumors become infiltrated with immune and inflammatory cells (39–41), blood endothelial cells (42), lymphatic endothelial cells (6), CAFs (43), the ECM (44) and bone marrow-derived mesenchymal stem cells (8) within the stroma. Crosstalk exists between tumor-associated stromal cells and tumor cells through signaling molecules to promote tumor invasion, metastasis, immunosuppression and to induce treatment resistance (45). Regulation of the active interaction between tumor cells and tumor-associated stromal cells (that interfere with IL-6 mediated crosstalk between tumor cells and CAFs) in the TME has shown promising antitumor effects in GC (46). The Xiaotan Sanjie decoction, a decoction that contains a plethora of phytochemical compounds (47–49), vitamins (50), and peptides (51–53) has demonstrated multiple actions on various soluble molecules, cytokines and growth factors released by parenchyma and stroma cells of GC. The Xiaotan Sanjie decoction shows activities on desmoplastic reactions (21,54,55), ECM formation and degradation (56,57), and tumor blood supply (58–61) through regulating these elements in the TME over the course of the GC progression.
Effects of the Xiaotan Sanjie decoction on CAFs
CAFs are a predominant stromal constituent within the TME and play a prominent part in tumor progression (62). The high proportion of CAFs was identified as a predictor of poor outcome in patients with GC in a meta-analysis (63). The fibroblast activation protein α (FAP) is highly expressed on CAFs and is rarely detected in normal stomach tissue. FAP upregulation has been reported as an indication for a worse prognosis in GC and has a significant effect on GC development, immunosuppression and drug resistance to immune checkpoint inhibitors (64). The Xiaotan Sanjie decoction downregulates FAP protein and mRNA expression in GC MKN-45 cells xenografted in nude mice (65).
TGF-β is a ubiquitous, pleiotropic cytokine that plays an important role in cancer development (66). Activation of the TGF-β signaling pathway is involved in gastric carcinogenesis in earlier and later stages; in addition, elevated serum TGF-β1 protein levels are predictors of lymph metastases and dissemination in the peritoneal cavity after gastrectomy (67). TGF-β plays an indispensable role in activation of resident quiescent fibroblasts, and differentiation of bone marrow-derived mesenchymal stem cells and adipose tissue-derived stem cells into CAFs (68–70). Inhibition of TGF-β signaling interrupts the differentiation of human MSCs to CAFs and abrogates their pro-tumorigenic function (71). TGF-β signaling includes a coordinated interaction between TGF-β receptor (TGFBR)1 and TGFBR2, which has been thoroughly described in the literature (66,72). TGF-β shows antitumor activities in the early stage and activity as a tumor promoter in the later stage of various cancer types, such as hepatocellular carcinoma, prostate cancer and GC (73,74). The antitumor activities of TGF-β are compromised by the loss or reduction of TGF-β receptor expression or of downstream signaling targets while the cancer progresses to an advanced stage (75,76). TGFBR2 gene is a putative tumor suppressor, and loss of function of TGFBR2 is closely correlated to progression in patients with GC (77–80). In an experimental study, the expression level of TGF-β was downregulated in serum of Xiaotan Sanjie decoction-treated nude mice with orthotopically transplanted GC tumors (21). The Xiaotan Sanjie decoction has been observed to exert antitumor effects by upregulating TGFBR2 in vivo and in vitro (22). Previous studies have suggested that the aqueous extracts of Fritillariae cirrhosae bulbus (54) and Sinapis semen (55), two herbal medicinal components of the Xiaotan Sanjie decoction, downregulate the activity of the TGF-β/SMAD signaling pathway. The aqueous extracts of scorpion (an animal medicinal product used in the decoction)-medicated serum significantly alleviates the TGF-β1-induced epithelial-mesenchymal transition (EMT) process (81). We hypothesize that the Xiaotan Sanjie decoction has the ability to decrease the formation of CAFs by interrupting the TGF-β signaling pathway.
Activated CAFs can secrete soluble molecules, including the upregulation of IL-6 in dysplastic stomach tissue, and is associated with GC development (46). IL-6 is a major mediator in cross-talking between tumor cells and CAFs in the TME (82). Notably, interruption of this interaction by genetic modification of IL-6 expression inhibits gastric tumor growth (46). In a Xiaotan Sanjie decoction-treated S180 tumor-bearing mice model, the expression levels of IL-6 decrease significantly in the tumor and adjacent tissues (83). Bioactive research has revealed that isolated compounds extracted from Galli gigerii endothelium corneum (84) and Glycyrrhiza uralensis Fisch (85), another two natural products in the Xiaotan Sanjie decoction, have the ability to downregulate expression of TNFα, IL-1 and IL-6.
The tumor-derived IL-8, also secreted by CAFs, actively participates in vascularity and tumorigenesis in gastric carcinoma cell lines in vitro (86). A meta-analysis concludes that IL-8 expression might be a poor prognosticator for GC (87). Overexpression of IL-8 located in CAFs is associated with resistance to cisplatin in patients with GC via NF-κB activation and ABCB1 upregulation (88). Ju et al (20) examined expression levels of IL-8 and its receptors in gastric tissue in S180 ×enograft-bearing mice treated using the Xiaotan Sanjie decoction. The IL-8 protein level was observed to be markedly decreased in tumor xenografts and neighboring gastric tissue. In another study, the Xiaotan Sanjie decoction has shown positive effects on inhibiting progression and metastatic behavior of SGC-7901 GC cells through downregulation of IL-8 (89). The Xiaotan Sanjie decoction, in combination with platinum-based chemotherapy may be able to achieve predictable benefits for patients with GC in the clinical setting.
Effects of Xiaotan Sanjie decoction on ECM
An altered ECM, which is the supporting structure of the TME, has a notable impact on the aggressiveness of cancer cell (6,42). CAFs play predominant roles in the production of structural macromolecules of ECM (such as collagen, fibronectin and laminin) as well as in the secretion of enzymes (such as lysyl hydroxylases and metalloproteinases) to degrade these structural components (90). TGF-β is an enhancer in the process of constructing a stiffened ECM by the CAFs (91,92). As previously discussed, the Xiaotan Sanjie decoction has been shown to downregulate activities of CAFs and to interfere with TGF-β signaling pathway (21,22,54,55). Therefore, the recipe may alleviate the excessive deposition of components of ECM, such as collagen, fibronectin and laminin, as well as prevent degradation of structural macromolecules of the ECM.
Hyaluronic acid (HA), an important component in the ECM, is expressed in numerous cancer types, including GC (93). A HA-positive tumor is a predictor of advanced disease and poor survival rate (94,95). HA plays an important role in limiting the delivery of therapeutic agents to tumor tissue (96,97). Hyaluronidase is associated with favorable antitumor effects in GC by degrading HA within the TME (98). Hyaluronidase activities have been found in venom extracted from Scorpion and Scolopendra, two natural animal products used in the Xiaotan Sanjie decoction (99,100).
CD44, a receptor for HA, collagen, fibronectin and growth factors, is a multifunctional receptor involved in cell-cell and cell-ECM interactions (101). High expression of CD44 variants on GC cells is associated with local tumor growth and metastatic spread in patients with GC (102). The HA-CD44 interaction has been suggested to induce uncontrolled proliferation, migration and drug resistance in various tumor types including metastatic breast tumor, ovarian tumor and GC in cellular studies (103). An animal study found significant differences in CD44V6 expression between the Xiaotan Sanjie decoction group and control group in a MKN-45 GC nude mouse model (23). Another study further confirmed the link between downregulation of expression of CD44V6 and the Jinlongshe formulae (Hospital-prepared Xiaotan Sanjie decoction) treatment (104).
Destruction of ECM and basement membrane barriers is a prerequisite for the metastasis of GC (105). The Xiaotan Sanjie decoction has shown the ability to prevent MMPs from degrading the ECM and its basement membrane in a MKN-45 GC nude mouse model (56). In an animal study, Sprague-Dawley rats were used to prepare the Xiaotan Sanjie decoction drug serum. The drug serum significantly inhibited the proliferative, metastatic and invasive ability of the human GC cell line SGC-7901. Protein and gene expression levels of MMP-9 were downregulated in this experiment (57).
Effects of Xiaotan Sanjie decoction on tumor vasculature
Increased vascularity and neoangiogenesis provide oxygen and nutrients for tumor growth and expansion with advancing cancer stages (15). VEGF and its receptor (VEGFR) are important elements to form a new blood vessel network. Activated CAFs serve as an important VEGF promoter that establish an abnormal vascular condition in the TME (106). In a study on stomach biopsy of 20 cases with GC, the effects of the Xiaotan Sanjie decoction on microvessel density (MVD) and VEGF-A/VEGFR-2 activities were evaluated in histopathological samples of GC and adjacent tissue. At 6 months, MVD and VEGF-A/VEGFR-2 expression levels were significantly decreased in samples from patients treated with the Xiaotan Sanjie decoction (58). Animal studies have also shown that the Xiaotan Sanjie decoction downregulates expression of VEGF, kinase insert domain receptor, VEGF-D protein and mRNA in comparison with 5-fluorouracil group in tumor xenografts mice to inhibit tumor metastasis (59,60). Xiaotan Sanjie decoction has also shown inhibition of the formation of vasculogenic mimicry, a distinct tumor microcirculation model that does not depend on endothelial cells (61).
Xiaotan Sanjie decoction is associated with favorable survival and quality of life in GC
The Xiaotan Sanjie decoction has been used to treat GC with good efficacy and safety profile for >20 years (17,32). The Xiaotan Sanjie decoction improves quality of life more compared with chemotherapy in patients with advanced GC who had undergone the subtotal or total gastrectomy proceedure (107–109). The Xiaotan Sanjie decoction has shown satisfactory outcomes in clinical studies that evaluated the effects of the decoction in combination of chemotherapy or other Chinese medicinal formulations on quality of life and overall survival in patients with advanced GC (110–113). In a clinical study, among patients with stage III and IV GC, those who were treated with the Xiaotan Sanjie decoction in combination with chemotherapy (Etoposide, Calcium Folinate and 5-Fluorouracil) had longer overall survival and 3-year survival compared with those who received chemotherapy only (110). In another study, efficacy of Xiaotan Sanjie decoction combined with Huangqi injection and Huachansu injection (both are traditional Chinese patent medicine) were observed in patients with advanced GC. The results showed that TCM can improve Karnofsky performance score, NK cell activity and CD3 and CD4 cells counts more compared with those of chemotherapy (5-Fluorouracil, Oxaliplatin, Vincristine, Cisplatin, Mitomycin) (111). The Xiaotan Sanjie decoction has been shown to have a well-established safety profile, provide an enhanced quality of life, improve tumor response and prolong survival time and Karnofsky performance score in patients with GC (112,113). Therefore, Xiaotan Sanjie decoction may be a promising candidate for use in collaboration with conventional treatment regimens as an alternative method to delay cancer progression.
Summary and perspectives
The TME in GC is a complex ecosystem that consists of newly formed blood and lymphatic vessels and diversified stromal cell types embedded in a modified ECM (8). Targeting the TME has revealed promising survival outcomes by inhibition of VEGF signaling pathway or PD1 signaling pathway in patients with GC (9–11). However, there is a gap between the complete understanding of the underlying molecular mechanisms of a plethora of interconnected molecules and pathways in the TME in GC and exactly how metastatic GC leads to death. More pivotal molecular pathways or cell types need to be revealed in the TME in GC to develop innovative therapeutic regimens.
For thousand years, Chinese physicians have used traditional natural medicine to treat a plethora of diseases, including GC. TCM formulations have notable effects on multiple targets and seldomly cause the occurrence of undesirable effects (26,28). In addition, they may provide long-term benefits for patients with GC (19). The therapeutic effect of TCM formulations on tumors has been demonstrated in multiple pathways, providing reasonable evidence for the ability to restore abnormal TME in GC back into balance (32). For >20 years, models have been established based on phlegm syndrome theory for GC (17). The biochemical properties of the TCM term ‘phlegm’ in GC may be partly described in modern medical language by way of a series of preclinical studies.
Contaminated phlegm is likely to be an important pathological product in the development of GC (114). The hypothesis regarding symptoms, signs and molecular profiles stems from the clinical and experimental observation that the TME in GC can share commonalities with phlegm syndrome (17,32,114). A TCM decoction, Xiaotan Sanjie decoction, has been formulated to treat the phlegm syndrome in patients with GC (17,32). As discussed, the Xiaotan Sanjie decoction has shown activities on CAFs (21,54,55,65), ECM (23,56,57,99,100,104) and the tumor blood supply (58–61) within the TME during tumorigenesis, growth and migration of GC in preclinical studies.
The Xiaotan Sanjie decoction inhibits GC initiation by upregulating TGFBR2 to normalize the antitumor action of the TGF-β/SMAD signaling pathway (22). At subsequent stages, the Xiaotan Sanjie decoction has revealed the ability to decrease the formation of CAFs through interruption of the expression of TGF-β (21). In the single-component studies, the aqueous extracts of Fritillariae cirrhosae bulbus (54) and Sinapis semen (55), two herbal medicinal compositions of Xiaotan Sanjie decoction, suppress the protumorigenic activity of TGF-β/SMAD signaling pathway. In addition, the aqueous extracts of scorpion-medicated serum significantly alleviates the TGF-β1-induced EMT process (81). The Xiaotan Sanjie decoction interferes with crosstalk between CAFs and tumor cells by downregulating IL-6 (83) and IL-8 (20,89) to inhibit tumor proliferation. Isolated compounds extracted from Galli gigerii endothelium corneum (84) and Glycyrrhiza uralensis Fisch (85), another two natural products in the Xiaotan Sanjie decoction, have the ability to downregulate expression of IL-6. Furthermore, the Xiaotan Sanjie decoction alleviates the development of deposition of ECM by blocking the activities of CAFs. The Xiaotan Sanjie decoction interrupts HA-CD44 interaction between ECM and tumor cells by degrading HA (99,100) and downregulating expression of CD44V6 (23,104). The Xiaotan Sanjie decoction has also been revealed to potentially target angiogenesis by downregulating the expression level of VEGF to exert antitumor effects (58–60). During advanced stages, the Xiaotan Sanjie decoction has demonstrated effects on GC tumor cell migration by preventing the degradation of the ECM and its basement membrane (56,57). The possible mechanisms of antitumor activities of the Xiaotan Sanjie decoction are summarized in Fig. 1.
The Xiaotan Sanjie decoction improves survivorship and quality of life in patients with advanced GC in clinical studies. However, it is difficult to compare these clinical outcomes to studies conducted to observe efficacy and safety of synthetic drugs or biological products in patients with GC because the sample size of clinical studies using the decoction is relatively small. Well-designed, prospective, large-scale clinical trials should be conducted to find the most appropriate niche of the Xiaotan Sanjie decoction in the treatment of patients with GC. However, a preliminary conclusion may be drawn that the Xiaotan Sanjie decoction targets CAFs, ECM and angiogenesis in the TME, and thereby the decoction prepared a preferable physical condition for chemoradiation therapy or immune therapy. Advanced technologies, including synthetic biology and scalable spatial analysis of the TME (115,116), are enabling novel methods for finding and exploiting the medicinal value of natural products. Therefore, this has the potential to define the conclusive role of the Xiaotan Sanjie decoction in the treatment of GC.
Acknowledgements
Not applicable.
Funding
This project was supported by grants from the National Natural Science Foundation of China (grant no. 82074168) and the Science and Technology Support Program of Shanghai Science and Technology Commission (grant no. 19401930400).
Availability of data and materials
Not applicable.
Authors' contributions
PKW and XQY developed the concept, designed the study and revised the manuscript. DZS collected the literature and wrote the draft. All authors have read and approved the final manuscript. Data sharing is not applicable.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Authors' information
Dr Da-Zhi Sun, ORCID ID: 0000-0002-7195-4931cz2016sdz.
Competing interests
The authors declare that they have no competing interests.
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