Periostin: A matricellular protein with a multifaceted role in tumorigenesis (Review)

Background

Cancer presents a considerable challenge in medical research due to its diversity and breadth. The proposal of cancer hallmarks attempts to convert the complexity of cancer into a set of provisional basic principles, which can help researchers understand the mechanisms underlying cancer development more comprehensively and logically. Cancer hallmarks are a set of capabilities acquired by human cells as they progress from a normal to a proliferative state, and are key to the malignant development of tumors (1). The tumor microenvironment (TME) is considered to carry out an important role in tumorigenesis and malignant progression. The TME is a dynamic environment that includes all non-cancerous and non-cellular components of a tumor, such as fibroblasts, immune cells, the extracellular matrix (ECM) and various secreted factors such as IL-6 and IFN-γ (2). Among these components (POSTN), a matricellular protein initially identified in bone and periodontal ligaments, has emerged as a multifunctional regulator in both physiological and pathological contexts (3). POSTN was initially discovered in 1993 (4), and numerous associated studies have since been conducted (5-11). Initially, POSTN was reported to be expressed minimally or not at all in the vast majority of mature tissues but, highly expressed in the context of disease states such as cancer, inflammation and fibrosis (12,13). Additionally, POSTN regulates the development and maturation of fibrous-rich embryonic tissues, such as heart valves and other periodontal ligaments (14,15).

In tumors, POSTN is a key player in tumor hallmarks such as proliferation, metastasis and immune evasion (12). POSTN achieves this through interactions with integrins and the activation of underlying downstream signaling pathways (1). Despite growing evidence associating POSTN with diverse cancer hallmarks, its isoform-specific functions, regulatory mechanisms within heterogeneous TME components and therapeutic potential remain incompletely characterized (16-22). An increasing number of preclinical and clinical studies have demonstrated the potential of POSTN in oncogenic mechanisms and as a biomarker (12,23-28). The present review primarily focuses on the latest research on the functional diversity of POSTN and its role in the tumor niche, which provides insights into therapeutic strategies.

Molecular structure of POSTN

Gene organization

Early studies of POSTN date back to 1993, when a gene was identified that encodes the 811 amino acid residue osteoblast-specific factor 2, later renamed as POSTN (4,29-31). The human POSTN gene, located on chromosome 13, spans 36,262 bp, contains 24 exons and encodes a protein of 836 amino acids (https://www.ncbi.nlm.nih.gov/gene/10631).

Alternative splicing

Selective splicing is a tightly regulated process that contributes to the high complexity of the multicellular eukaryotic transcriptome at the protein level. Various studies have revealed that in several species, there is alternative splicing of the POSTN gene in either insertion or deletion patterns (4,32-34), In humans, exons 17, 18, 19 and 21 of the POSTN gene are selectively spliced, resulting in a variety of isoforms. Moreover, other isoforms of the POSTN gene, including 10 variants of unknown function, have also been discovered in various types of cancer such as renal cell carcinoma and non-small cell lung cancer (32,35). Among the physiologically expressed POSTN isoforms, PN4 (POSTN lacking exons 17 and 21) is ubiquitously expressed and predominant (34). Several studies have discovered new isoforms and explored their possible roles (18,36-41). Additionally, POSTN3 containing exon 17 and 21 (but not containing exon 12) has been shown to promote the growth and metastasis of breast cancer tumors through alternative splicing (34). Similarly, although POSTN is a suppressor in bladder cancer, POSTN variant I, which is highly expressed in bladder cancer, does not exhibit a suppressive effect (42).

Structural domains of POSTN

POSTN is a disulfide-linked 90 kDa protein secreted by osteoblasts and osteoclast-like cell lines (8). The protein consists of six structural domains, including a cysteine-rich Egf-like module containing Mucin-like hormone receptor-like structural domain, four tandemly repeated FAS-1 structural domains and a hydrophilic C-terminal structural domain (4) (Fig. 1). The four-repeat fasciclin structural domain has homology to insect proteins, based on which the Fas1 structural domain characterizes it as a member of the fasciclin 1 family. The FAS-1 structural domain has been shown to interact with fibronectin (43), tenascin-C (44), bone morphogenetic protein-1 (45) and Cellular Communication Network factor 3 (46). As an ECM protein, POSTN relies largely on the FAS-1 structural domain to bind to integrins and thus mediate various signaling pathways (47). The C-terminal structural domain, conversely, lacks known functional domains and is intrinsically disordered (48).

Figure 1 Structure of POSTN. POSTN consists of six structural domains, including EMI domain, four tandemly repeated FAS-1 structural domains and a hydrophilic C-terminal structural domain. N, N-terminal; CTD, C-terminal domain; POSTN, periostin; EMI, Egf-like module containing Mucin-like hormone receptor-like; FAS, Fasciclin.

Expression of POSTN

Physiological expression of POSTN

POSTN is a matrix protein that is named after its preferential expression in mouse periosteum and periodontal ligaments. The expression of POSTN in these tissues is regulated by mechanical stresses (49). Physiologically expressed in collagen-rich connective tissues (such as, cardiac valves, tendons and lungs), POSTN becomes active during fetal development but is predominantly absent or minimally expressed in the majority of adult tissues. It regulates tissue maturation in embryonic structures such as the periosteum, periodontal ligaments, liver, kidneys and ureters (14,50). Notably, POSTN drives fetal cardiomyocyte lineage differentiation and heart valve maturation (15), positioning it as a potential biomarker for prenatal non-invasive screening of congenital heart defects. Additionally, elevated POSTN expression occurs in stem cell niches of adult organs, including the mammary gland, intestine, spleen, bone and skin, suggesting context-dependent roles in tissue homeostasis.

Pathological expression of POSTN

POSTN and its variants are differentially expressed and are upregulated in inflammation, sites of injury and tumors (18,51,52). POSTN contributes to pathological processes such as allergy, inflammation, tissue remodeling, regeneration, fibrosis and tumor progression. For example, POSTN is a valuable biomarker of type 2 inflammation (a specific type of immune response that is primarily mediated by type 2 helper T cells)as a downstream molecule of IL-4 and IL-13, which has been closely associated with the pathogenesis of asthma (53), chronic rhinosinusitis (54), allergic dermatitis (55) and pulmonary fibrosis (56). In addition, POSTN is also involved in the development of myocardial infarction through its response to TGF-β in inflammation and fibrosis in chronic liver and kidney disease (57), as well as through its interaction with other ECM proteins (for example, fibronectin, heparin and Tenascin-C) (58).

POSTN is expressed in several primary types of cancer, including breast, bladder, colon, pancreatic and ovarian cancer, as well as non-small cell lung and oral cancer (13,59) (Table I). For example, POSTN is expressed at low levels in normal breast tissue, but high expression of POSTN is often detected in breast cancer, with the average expression level of the periosteal protein being 20-fold higher compared with the baseline expression level defined by gene array data for normal breast tissue (60). POSTN is also abnormally elevated in metastatic cancer types, most notably liver metastases from colorectal cancer, which has been associated with a supportive fibrotic microenvironment promoted by both POSTN and TGF-β1 (61). However, the upregulation of POSTN expression in tumors is not universal. For example, POSTN is not expressed in hematologic malignancies such as leukemia and myeloma (62).

Table I POSTN-related signaling pathways in malignant tumor progression.

Table I

POSTN-related signaling pathways in malignant tumor progression.

Authors, year	Pathway	Cancer type	POSTN function	Associated cells	(Refs.)
Ribatti et al, 2007	POSTN/α6β4	Pancreatic cancer	Promotes invasiveness and survival	CAFs	(87)
Parker et al, 2020; Erkan et al, 2009; Halperin et al, 2022; Mouw et al, 2014; Boulter et al, 2021	POSTN/αvβ3, αvβ5	Breast cancer, ovarian cancer, esophageal squamous cell carcinoma, Glioblastoma and glioma	Regulate adhesion, migration;	TAM, CAFs	(72,100,116,162,163)
Baril et al, 2007; Boulter et al, 2021; Xu et al, 2016	POSTN/PI3K/Akt	Non-small-cell lung cancer, colon cancer and cholangiocarcinoma	Promote cell proliferation, invasion and migration	CAFs	(88,163,166)
Shao et al, 2004; Zhou et al, 2015; Ashley et al, 2017	POSTN/TGF-β	Hepatocellular carcinoma, Ovarian cancer and colorectal cancer	Promotes transformation and maintenance of CSCs; promotes metastasis	Macrophage, CAFs	(60,101,167)
Zhou et al, 2015; Halperin et al, 2022; Kiesler et al, 2024; Jamaluddin et al, 2018	POSTN/NF-κB	Ovarian cancer, breast cancer, colorectal cancer and glioblastoma	Promotes cancer metastasis	M2 macrophage, CAFs	(101,116,168,169)
Nielsen et al, 2016; Muscarella et al, 2021	MAPK/ERK	Triple-negative breast cancer, glioblastoma	Enhance invasion, migration, stemness, growth; chemoresistance	CSCs	(170,173)
Moniuszko et al, 2024	POSTN/Wnt	Neuroblastoma	Promotes invasion, adhesion and growth	CSCs	(66)
Huang et al, 2024; Wang et al, 2022	POSTN/FAK	Colorectal cancer, papillary thyroid tumor	Promotes tumorigenesis	CAFs	(67,102)

[i] CAFs, cancer-associated fibroblasts; TAM, tumor-associated macrophage; CSCs, cancer stem cells; POSTN, periostin.

Role of POSTN in the hallmarks of cancer

Cancer development is a multistep process initiated by oncogenic mutations that confer clonal advantage, ultimately driven by genomic instability (63). This progression is marked by acquired hallmarks including sustained proliferation, evasion of growth suppression, resistance to apoptosis, replicative immortality, angiogenesis, invasion/metastasis, metabolic reprogramming and immune escape. Emerging features such as phenotypic plasticity, epigenetic dysregulation, microbiome interactions and senescence further define tumorigenesis (1). Notably, POSTN overexpression and its alternatively spliced isoforms (such as, in renal, lung, breast and gastrointestinal cancer) regulate multiple oncogenic processes (13,40,64).

Cell proliferation

Cell proliferation is a process regulated by the synergistic action of mitogenic growth-promoting and antiproliferative signals (65). POSTN has been shown to induce proliferation in a variety of tumors. For example, POSTN can interact with the classical Wnt signaling pathway to promote colorectal tumorigenesis (66) and proliferation in neuroblastoma (67). POSTN from tumor stromal fibroblasts promotes colorectal carcinogenesis by activating YAP/TAZ through the Integrin-focal adhesion kinase (FAK)-Src signaling pathway (19). POSTN also promotes gastric cancer proliferation studies revealed that POSTN enhances the proliferation of OCUM-2MLN and OCUM-12 diffuse gastric cancer cell lines in vitro through activation of ERK, intuitively, tumor growth in POSTN (−/−) mice is markedly slower compared with that in wild-type mice (68). POSTN-promoted proliferation of tumor cells is also exemplified in carcinomas such as the A549 lung carcinoma cell line (69), triple-negative breast carcinoma (17) and melanoma (70).

However, POSTN activity is not exclusively associated with tumor growth. Shao et al (60) established stable POSTN-overexpressing cell lines using three POSTN-deficient tumor models, demonstrating that POSTN overexpression did not alter proliferation rates under in vitro culture conditions but considerably enhanced invasive capacity.

Activating invasion and metastasis

Besides promoting cell proliferation, POSTN also carries out a key role in activating invasion and metastasis. Tumor invasion and metastasis are an inefficient process requiring the overcoming of several rate-limiting steps, the occurrence of which often portends malignancy and a poor prognosis (71). Due to the heterogeneity of tumor cells, tumor invasion and metastasis are difficult to treat and remain one of the major challenges in the field of tumor therapy (72).

Epithelial-mesenchymal transition (EMT), initially identified during embryogenesis, is now recognized as a key driver of developmental processes, disease progression and tumor invasion (73). POSTN is involved in tumor invasion and metastasis by regulating EMT, the classical way of which is that POSTN binds to integrins and activates Akt/PKB and FAK-mediated signaling pathways (13). Studies demonstrate that stromal POSTN expression in ovarian cancer promotes tumor invasion and metastasis via PI3K/Akt pathway activation, mechanistically driving EMT (27,74,75). POSTN activates STAT3 signaling to modulate EMT markers such as caveolin-1 and angiogenesis-related genes such as HIF-1α and vascular endothelial growth factor-A (VEGF-A), with its knockdown shown to reverse glioblastoma stem cell (GSC) resistance to anti-VEGF-A therapy (76). POSTN has also been demonstrated to induce EMT in hepatoblastoma (77) and prostate cancer (78). Moreover, POSTN can inhibit specific targeted microRNAs (miRNAs) involved in the regulation of EMT. miRNAs are small endogenous RNAs that post-transcriptionally regulate gene expression and may target up to one-third of human mRNAs (79). Song et al (80) found that the POSTN gene was markedly upregulated in the gastric cancer cell line SGC-7901 treated with miR-148b mimic, which suggests the possible involvement of POSTN in the pathways related to the development and progression of gastric cancer. In lung cancer, POSTN promotes EMT through the MAPK/miR-381 axis (81).

POSTN promotes cell motility to promote tumor metastasis. It was demonstrated that secretion of POSTN by von Hippel-Lindau oncogene non-expressing (VHL-) cells enhanced the motility of VHL-WT cells and promoted vascular escape in clear cell renal cell carcinoma tumor cells (82). In a study on colorectal cancer, POSTN was found to activate FAK and AKT or STAT3, accelerating metastasis and activating migration of tumor and stromal cells through stromal remodeling capacity (83). These studies suggest that POSTN carries out an important role in the development of the TME and that increased expression of POSTN in the stroma is somewhat indicative of tumor stage and prognosis (84).

Interestingly, POSTN largely promotes tumor-invasive metastasis, yet it is regarded as a tumor suppressor in bladder cancer (85). This may be associated with the selective sharing of POSTN. Of the two splicing variations of POSTN (variants I and II) isolated from bladder cancer, Variant II has key domains that interact with matrix proteins such as integrins, inhibiting cancer cell invasion and metastasis. While Variant I, lacking certain exons, has a changed structure that weakens these interactions, losing its inhibitory function and potentially promoting cancer progression (42).

Inducing vasculature

Tumor angiogenesis enables nutrient and oxygen delivery to growing malignancies, with aberrant vascular features, such as disorganized architecture, sinusoidal vessel formation and functional heterogeneity, distinguishing tumor vasculature from normal tissues (86). VEGF is a central driver of angiogenesis, which binds tyrosine kinase receptors Flt-1 and Flk-1/KDR to initiate signaling. POSTN has been identified as a pro-angiogenic factor that facilitates tumor neovascularization via 'vascular co-option', exploiting pre-existing vessels in adjacent healthy tissues (87). When the tumor volume is >2 mm3, increased expression of POSTN enhances the resistance of cancer cells to hypoxic conditions (88). For instance, in colorectal cancer, POSTN activates the Akt/PKB pathway to increase endothelial cell survival and vascular proliferation, correlating with metastasis and serving as a prognostic marker (89). Similarly, ovarian cancer studies reveal that POSTN overexpression drives angiogenesis and metastatic spread (11,90-92). Mechanistically, POSTN upregulates Flk-1/KDR expression in endothelial cells via integrin αvβ3-FAK signaling, a pathway associated with breast cancer progression (22,60).

POSTN also promotes lymphangiogenesis, a key step in metastatic dissemination. Gillot et al (93) demonstrated that POSTN enhances VEGF-C-mediated lymphangiogenesis and primes lymph nodes for metastatic colonization. In head and neck squamous cell carcinoma (HNSCC), POSTN drives lymphatic remodeling through dual mechanisms: Indirect upregulation of VEGF-C mRNA and direct activation of Src/Akt pathways. This aligns with observed associations between POSTN-overexpressing xenografts and lymphatic involvement in HNSCC (94). Collectively, POSTN orchestrates tumor vascularization and lymphatic network expansion, fostering metastatic efficiency.

Evasion of apoptosis

Apoptosis is a regulated form of programmed cell death, which carries out dual roles in tumor biology. Its dysregulation contributes to tumor progression, therapy resistance and metabolic reprogramming by enabling uncontrolled proliferation or insufficient apoptosis (95). Apoptosis also interacts with tumor metabolism to collectively drive malignancy (96). Notably, apoptosis can paradoxically support tumor survival through microenvironmental interactions (97). Emerging concepts such as pan-apoptosis (combined apoptosis-necroptosis) further highlight the complexity of apoptosis regulation in cancer immunity (98).

ECM protein POSTN enhances tumor cell survival under stress conditions (hypoxia, nutrient deprivation). Mechanistically, POSTN activates β4 integrin/PI3K and Akt/PKB pathways to suppress apoptosis in pancreatic, colorectal and non-small cell lung cancer (88,89,99). In hypoxic pancreatic tumors, POSTN drives a pathological cycle: Hypoxia induces stellate cells to secrete POSTN, which sustains fibrosis and cellular viability while exacerbating hypoxia (100). This ECM-mediated adaptation enables tumor persistence across multiple cancer types by counteracting environmental stressors and death signals.

Avoiding immune destruction

Immunomodulation carries out an important role in tumor development and signaling between POSTN and immune cells can take place, thus carrying out a role in the immune escape of tumors. A study noted that GSCs in glioblastoma multiforme (GBM) secrete POSTN, which can recruit M2-type tumor-associated macrophages (TAMs) to support GBM growth (101). Similarly, POSTN can promote ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts (CAFs) through integrin-mediated NF-κB and TGF-β2 signaling (74). Wang et al (102) discovered that POSTN+ CAFs can recruit secreted phosphoprotein 1 (SPP1)+ macrophages and trigger an increase in SPP1 expression via the IL-6/STAT3 signaling pathway, thereby enhancing therapeutic resistance in hepatocellular carcinoma (HCC). In addition, a recent study have shown that thyroid tumor cells and CAFs can promote tumor development through crosstalk between IL-4 and POSTN (103). The aforementioned studies may suggest new targets for cancer inhibition.

Cellular senescence

Cell senescence is a stress-induced stable growth arrest that has been regarded as a passive bystander in the cessation of proliferation. However, research over the past decade suggests that senescence also serves as the foundation for tissue development and function (104-107). For tumors, cellular senescence has two opposing functions. Firstly, senescence halts the cell cycle, thereby preventing the formation of malignant tumor cells and promoting tissue regeneration and repair (108). Secondly, senescent cells present in the TME can induce persistent inflammatory states and reprogram the TME (109) through the production of the senescence-associated secretory phenotype, thereby promoting tumor growth, metastasis and drug resistance (110). There is currently evidence suggesting an association between POSTN and cellular senescence, warranting further investigation. Zhu et al (111) experiments indicate that POSTN may promote nucleus pulposus cell senescence and ECM metabolism by activating the NF-κB and Wnt/β-catenin signaling pathways, carrying out a notable role in the progression of disc degeneration. Overexpression of POSTN simultaneously leads to fibrosis and senescence of cardiomyocytes (112). Similarly, POSTN has been revealed to promote kidney aging by participating in fibrosis and lipid metabolism (113). Huang et al (114) used RNA-Sequencing technology to examine gene expression changes in primary skin fibroblasts from healthy controls and patients with pyrroloquinoline quinone reductase 1 (PYCR1) mutations, and found that POSTN was one of the most downregulated candidate genes. To the best of our knowledge, although no published articles have yet described how POSTN influences cancer development through aging, the aforementioned discussions provide potential avenues for future research in this direction.

Epigenetic reprogramming

Epigenetic and metabolic reprogramming are closely related and mutually regulate each other, driving immune escape or hindering immune surveillance in certain cases, and carrying out an important role in tumor progression (115). CAFs are recognized as key components of the TME, which are stable at the genomic level but differ considerably from normal stromal precursors (116). The transformation of normal fibroblasts into CAFs involves extensive methylation changes, which can be induced by various factors such as TGFβ and pro-inflammatory cytokines such as leukemia inhibitory factor (117,118). The epigenetic modifications in CAFs not only activate and maintain their pro-invasive phenotype (118) but also enhances glycolysis in tumor metabolism. Becker et al (119) demonstrated that the epigenetic reprogramming of CAFs disrupts glucose metabolism and promotes breast cancer progression. Additionally, studies have elucidated the promotional role of the epigenetics of CAFs in prostate cancer (120) and bladder urothelial carcinoma (121). POSTN carries out an important role as a marker of CAFs in this process. Han et al (122) reported that POSTN is one of the DNA methylation biomarkers of nasopharyngeal carcinoma and patients with high POSTN expression have shorter overall survival times. The methylation of POSTN is also associated with the molecular mechanisms of important pathways associated with glioblastoma formation and patient overall survival (123).

POSTN is a multifunctional, pleiotropic molecule in cancer, with its effects exhibiting high context-dependence. It serves as a potent 'oncogenic factor' while also potentially assuming the complex role of a 'potential collaborator' under specific conditions, with the underlying core being the dynamic changes in TME (124,125). First, cancer of different tissue origins and molecular subtypes exhibit considerable differences in their TME. POSTN can be secreted by various cell types (such as, tumor cells and CAFs) and its effects may depend on the source cells as well as the specific receptors and downstream signaling pathways with which it interacts. POSTN typically promotes immune suppression; however, in certain contexts (such as specific immunotherapy combinations), the immune cells it recruits may unexpectedly alter the balance of the TME, potentially producing effects favorable to therapeutic response. This is not a direct 'beneficial' effect but an indirect outcome of specific contextual factors (126). Additionally, different splice variants of POSTN can have opposed effects, as demonstrated in bladder cancer (85).

Role of POSTN in the TME

Cancer is driven by the accumulation of mutations in cancerous cells but is not exclusively genetically determined. The majority of cancer types (90-95%) occur in close association with the environmental exposures and lifestyle choices of an individual, while genetic factors account for only a small proportion (5-10%) of all cancer cases (127).

TME refers to all the non-cancerous cells and non-cellular components in a tumor, which can be regarded as a special ecological niche where tumor cells are located. The cellular components include fibroblasts, adipocytes, endothelial cells, infiltrating immune cells such as lymphocytes and dendritic cells; while the non-cellular components include ECM and soluble components such as hormones, growth factors or cytokines (12). These components were previously considered 'innocent bystanders', but several studies have revealed that constant, reciprocal and dynamic interactions between tumor cells and the TME (2,128) are key in the cancer process (129) (Fig. 2). Current evidence suggests that POSTN activates key downstream signaling pathways by interacting with its receptor integrin, remodels the ECM by interacting with other ECM proteins [such as type I collagen, fibronectin, tenascin C and thrombospondin 1 (TSP-10)] (44) and remodels TME by cross-talking with other signaling molecules and recruiting inflammatory and immune cells (3).

Figure 2 Roles of POSTN in the development of malignant cancer. POSTN is a key driver of tumor progression and metastasis. It promotes cancer stem cell proliferation via the POSTN/TGF-β pathway and induces angiogenesis through VEGFR2. POSTN recruits stromal cells to form a fibrotic, immunosuppressive tumor microenvironment that supports tumor growth, protects disseminated tumor cells, and facilitates invasion. Furthermore, POSTN contributes to the formation of pre-metastatic niches and bone marrow colonization, enabling DTC dormancy and outgrowth. MDSC, myeloid-derived suppressor cells; HSCs, hematopoietic stem cells; DTC, disseminated tumor cell; EV, extracellular vesicle; CAFs, cancer-associated fibroblasts; NK, natural killer; POSTN, periostin; PMN, pre-metastatic niche.

POSTN in the metastatic niche

Tumor metastasis is an inefficient process where the majority of disseminated cells die, with only rare cells successfully colonizing distant sites. Emerging evidence implicates cancer stem cells (CSCs) as key drivers of metastasis, facilitated by interactions with the metastatic niche (130-133). Stromal fibroblast-derived POSTN, a component of normal stem cell niches, mediates CSC-niche crosstalk, as demonstrated by Malanchi et al (134). In metastatic tissues, POSTN is primarily secreted by CAFs, which are activated by paracrine or autocrine signals to coordinate metastasis through direct interactions with tumor cells and stromal components (135). For example, in colorectal cancer, POSTN overexpression in hepatic metastatic niches promotes tumor cell survival, angiogenesis and metastasis via the Akt/PKB pathway (89). Similarly, cervical squamous cell carcinoma studies reveal that POSTN+ CAFs disrupt lymphatic endothelial barriers by activating integrin-FAK/Src-VE-calmodulin signaling, facilitating dissemination (136-138). In ovarian cancer, POSTN drives metastasis through autocrine NF-κB/TGF-β2 activation in tumor cells and by recruiting M2 macrophages and CAFs. Stromal POSTN also enhances metastatic infiltration in skin and head-neck squamous carcinomas (74). Furthermore, POSTN can synergize with TNC, for example, POSTN may aggregate Wnt for stem cells, while TNC may enhance the response of these cells to Wnt and Notch (139) are 'two sides of the same metastatic ecological niche'.

POSTN in the CSC niche

CSCs or tumor-initiating cells, drive tumor heterogeneity through self-renewal, clonal initiation and long-term repopulation capabilities. The CSC niche preserves these properties, shields CSCs from immune surveillance and facilitates metastasis (132). As highlighted by Malanchi et al (134), CD90+CD24+ breast CSCs from primary tumors metastasize to the lungs and activate CAFs to secrete POSTN. This stromal POSTN recruits Wnt ligands into CSCs, amplifying Wnt signaling to fuel CSC expansion and metastatic colonization. In basal-like breast carcinoma, POSTN maintains CSC traits and mesenchymal phenotypes by regulating NF-κB-dependent cytokines (IL4 and IL8) via ERK signaling, thereby promoting metastasis (140). Similarly, ovarian cancer studies show that POSTN enhances CSC stemness, increasing invasiveness, therapy resistance and recurrence (20,27,74,90,141). In colon cancer, high Wnt activity defines CSC stemness (142) and POSTN interacts with Wnt ligands (Wnt1/Wnt3A) in colon CSCs, suggesting its role in reinforcing stemness (143). Further supporting this paradigm, Chen et al (144) identified a POSTN/TGF-β1 positive feedback loop in HCC. Through analysis of 110 HCC patient tissues and xenograft models, this study demonstrated that POSTN/TGF-β1 activates AP-2α transcription to sustain HCC CSC stemness and accelerate malignancy.

POSTN in the perivascular niche

Perivascular niche is key for maintaining both hematopoietic stem cells and CSCs, serving as a dynamic hub in cancer evolution (83). This niche context-dependently regulates tumor dormancy, metastatic spread, stemness and immune evasion, shaping tumor progression (145). Tumor cells exploit this niche to invade blood vessels (extravasation), a process involving endothelial cell contractility (via myosin) and mechanical interactions with the subendothelial matrix (146). However, disseminated tumor cells (DTCs) often face suppression in secondary organs, with only a subset surviving or entering dormancy. DTC 'awakening' represents a key rate-limiting step for metastasis. Stable vasculature suppresses proliferation through stromal TSP-1, while sprouting neo vessels exhibit pro-metastatic properties: Their endothelial cells upregulate POSTN, tenascin-C, fibronectin and TGF-β1, creating a microenvironment that drives tumor reactivation (3,147-149).

The perivascular niche also modulates immunity by facilitating immune cell infiltration. Perivascular TAMs promote angiogenesis, immunosuppression and tumor survival (150). POSTN recruits TAMs to remodel this niche, as seen in GBM, where GSCs secrete POSTN to attract and polarize TAMs toward the pro-tumor M2 subtype. This POSTN-mediated crosstalk sustains GSC-TAM clustering in perivascular regions, fostering therapy resistance and recurrence (101,151,152). These dual roles, structural support for metastasis and immunomodulation, highlight the perivascular niche as a promising therapeutic target.

POSTN in the pre-metastatic niche (PMN)

PMN, consisting of distinct resident cell types, ECM components and infiltrating cell populations, is a microenvironment induced by tumors in distant tissues that can provide a conducive environment for the proliferation of incoming tumor cells (153). It is currently considered that distant sites can be reprogrammed into the PMN by extracellular vesicles (EVs) carrying tumor-secreted factors. Potential mechanisms include enhanced angiogenesis and vascular remodeling, stromal remodeling, inhibitory effects of EVs on immune cells and alteration of the metabolic milieu. Formation of PMN is an integrative process that extends from the local to the systemic level (146,154,155).

POSTN can be induced by tumor products that reach distant tissues first and participate in pre-metastatic ecological niche formation (134). A study using lung fibroblasts isolated from the lung tissues of C5BL/6 J mice revealed that CAF EVs induced pre-metastatic ecotone formation in the SACC lungs of mice and demonstrated more robust matrix remodeling than SACC EVs. This may be due to POSTN activation of the TGF-β signaling pathway in lung fibroblasts (156). Previous studies reveal multifaceted roles of POSTN in pre-metastatic niche formation: Tumor-derived EVs deliver lncRNA MALAT1 to mediate M2 macrophage polarization via the POSTN/Hippo/YAP axis in triple-negative breast cancer (157), while colorectal cancer EVs carrying ITGBL1 reprogram fibroblasts to prime metastatic sites (158). POSTN facilitates immunosuppression by engaging myeloid-derived suppressor cells in tumor immune evasion (159) and promotes niche establishment through trauma-induced secretion in melanoma (160). Exosome-mediated POSTN transfer modifies distant tissue microenvironments (99), with elevated exosomal POSTN levels in thyroid cancer patients directly accelerating progression via niche remodeling (161).

POSTN in the fibrotic niche

Formation of a fibrotic microenvironment is associated with a series of events, including tissue injury, inflammation, myofibroblast differentiation and ultimately the excessive deposition of ECM components. The ECM comprises fibrous proteins and glycoproteins, forming a dynamic 3D structure that regulates cell adhesion, migration, tissue repair and disease processes through mechanotransduction (162,163). POSTN promotes fibrosis in pathological and cancer contexts, by interacting with soluble factors to induce myofibroblast differentiation (61,164). Activated myofibroblasts secrete a large amount of ECM components, primarily collagen, elastin and glycosaminoglycans (165).

The formation of fibrotic niches is key for tumor metastasis and the growth of tumors characterized by fibroproliferation. POSTN is one of the markers of fibrotic niches and it primarily functions through interactions with key signaling pathways such as TGF-β1 (61) and Wnt/β-catenin (166). Elevated POSTN levels in melanoma lung metastases associate with bleomycin-induced pulmonary fibrosis progression (167). In uterine fibroids, POSTN acts as both a biomarker and a therapeutic target by stimulating collagen overproduction and myometrial cell transformation (168,169). Additionally, metastasis-associated macrophages activate hepatic stellate cells via granulin secretion, generating POSTN-producing myofibroblasts that remodel liver stroma for tumor growth (170).

POSTN in the bone marrow microenvironment

Bone is a frequent metastatic site for solid tumors (for example, breast, prostate and lung cancer) (171,172). Bone marrow, a semi-solid tissue within bone cavities, facilitates hematopoiesis via hematopoietic stem cells and comprises cellular components such as mesenchymal stromal cells, osteoblasts and immune cells, as well as non-cellular elements including cytokines and growth factors (173,174). This microenvironment protects DTCs during colonization, dormancy and growth, and contributes to hematologic malignancies such as leukemia and myeloma (175,176).

POSTN is associated with bone metastasis. In breast cancer, BMSC-derived POSTN promotes bone metastasis, with murine models showing an 8-fold POSTN increase at metastasis sites compared with controls (177,178). Contrastingly, C-terminal intact periosteal protein (iPTN) levels decrease in breast cancer bone metastases due to histone K cleavage, suggesting iPTN as a potential biomarker for bone recurrence detection (179). POSTN also drives HNSCC progression via BMSC-induced PI3K/Akt/mTOR pathway activation (180). In multiple myeloma, elevated POSTN levels are associated with advanced disease severity, such as International Staging System stage 3 (181) and with dysregulation of bone metabolism, including an inverse relationship with bone formation markers and a positive correlation with bone resorption markers (182). Additionally, POSTN facilitates prostate cancer bone metastasis via integrin-mediated interactions with osteoblasts and tumor cells (183) and supports B-cell Acute Lymphoblastic Leukemia cell proliferation in the bone marrow niche (184).

Clinical translation of POSTN: Biomarker value and therapeutic targeting prospects

Although extensive basic research has confirmed that POSTN carries a central role in various pathological processes (185-187), its successful translation from a basic molecular marker to a clinically useful tool remains challenging. Currently, the practical application value of POSTN as a clinical biomarker is still under investigation, and there remains a notable gap between its potential applications and clinical practice.

POSTN as a diagnostic and prognostic biomarker

Since the pathological expression levels of POSTN are markedly higher when compared with normal expression levels (64,188), POSTN has potential as a diagnostic and prognostic biomarker for diseases. Since the upregulation of POSTN is not specific to any particular disease, this may limit its application as a standalone diagnostic biomarker. Currently, research is focused on combining POSTN with other biomarkers to develop more precise diagnostic and prognostic prediction models. A study demonstrated that the combination of plasma POSTN and CA19.9 considerably improved the sensitivity, specificity and AUC for diagnosing cholangiocarcinoma compared with using a single marker, reaching 87 and 91%, and 0.94, respectively (plasma POSTN: 78 and 85%, and 0.86; CA19.9: 67 and 90%, and 0.86) (189). Jia et al (25) demonstrated that, to distinguish healthy controls from locally advanced BCa, POSTN exhibited the highest AUC (AUCPOSTN=0.72, AUCCA153=0.57 and AUCCEA=0.62), and the AUC of CA153 and CEA were markedly improved when used in combination with POSTN. Furthermore, multiple studies have demonstrated that elevated serum POSTN levels are associated with worse overall survival and progression-free survival (7,190-193). In summary, the potential role of POSTN as a diagnostic and prognostic biomarker holds clinical value.

Subtype-specific strategies

With the advent of the era of precision medicine, accurate identification of subtypes has become increasingly important. In various types of tumors, the 'POSTN+' subtype is typically associated with features such as stromal proliferation, EM and TM characteristics (17,102,126). Patients with this subtype often exhibit greater invasiveness, increased metastasis risk and worse response rates to conventional chemotherapy. By contrast, the 'POSTN-' subtype is associated with relatively improved prognosis. Zhang et al (141) revealed that the stroma markedly contributes to the molecular classification of the mesenchymal subtype in high-grade serous ovarian cancer, with POSTN being one of the genes predominantly expressed in the stroma. In osteosarcoma, POSTN-positive expression is notably associated with histological subtype (P=0.000), Enneking staging (P=0.027) and tumor size (P=0.009) (194).

In invasive basal cell carcinoma (BBC), the two upregulated genes POSTN and WISP1 were validated at the protein level as being associated with invasive BCC (195). This subtype classification lays the foundation for developing precision strategies. A molecular typing kit based on POSTN expression levels could be developed to identify high-risk patient groups, guiding more intensive follow-up and early intervention. In terms of treatment, it provides a basis for achieving stratified therapy. Patients with high POSTN expression in this subtype may be the optimal candidate population for targeted therapies targeting the POSTN pathway itself or its downstream effector molecules or for immunotherapies targeting the immunosuppressive microenvironment.

Additionally, new CAF subtypes can be defined based on POSTN expression levels. Wang et al (102) recently found that high infiltration of POSTN+ CAFs and SPP1+ macrophages is associated with resistance to immunotherapy. For example, a study identified five CAF subtypes in gastric cancer, revealing that the CAF_0 subtype was highly associated with poor prognosis, with POSTN being the most notable marker gene for this subtype (196). These findings suggest that targeting specific CAF subpopulations may have potential benefits for improving clinical responses to immunotherapy.

Therapeutic clinical outlook

Targeted therapy for POSTN has progressed from the proof-of-concept stage to practical application. In preclinical studies, various targeted strategies have shown great promise. For example, PNX-001 (a humanized anti-POSTN monoclonal antibody) effectively blocks the interaction between POSTN and integrin in preclinical models, inhibits tumor growth and metastasis, and enhances the delivery of chemotherapy drugs (197). Another neutralizing monoclonal antibody targeting POSTN (MZ-1) has been shown to have a considerable growth-inhibitory effect on a subgroup of invasive ovarian tumors that overexpress POSTN (198). PNDA-3 (human osteopontin-3) is a DNA aptamer that selectively binds to the FAS-1 domain of POSTN, disrupting its interaction with its cell surface receptors αvβ3 and αvβ5 integrins, thereby markedly reducing primary tumor growth and distant metastasis (199,200).

Due to the increasing number of POSTN-related diseases, several clinical trials are currently underway. However, therapies targeting POSTN in the field of oncology remain at a relatively early stage, with very limited publicly available clinical data. Key future challenges include: Determining the optimal treatment window, selecting appropriate biomarkers to screen for patient populations likely to respond and exploring combination strategies with other therapies (such as immune checkpoint inhibitors, anti-angiogenic drugs) to overcome the complexity of the TME.

Future challenges and possible solutions

Despite considerable progress in POSTN research, there remain notable knowledge gaps and technical limitations in this field, which hinder its clinical translation process. First, there are conflicting data in the existing literature. In certain types of cancer, high POSTN expression is associated with poor prognosis [such as, breast cancer (13,128,130,139), glioblastoma (101,123), ovarian cancer (20,27,74,91,141) and liver cancer (13,62,71,89,193), but in other types of cancer (201,202), such as estrogen receptor-negative (ER-) or progesterone receptor-negative (PR-) phenotypes of breast cancer (203), its expression levels show only a modest association with clinical outcomes (203-205). These inconsistencies may stem from methodological heterogeneity, differences in patient cohorts and variations in the cellular origin and tissue localization of POSTN within the TME. Typically, POSTN is present in the ECM, while the main presence of POSTN in tumor tissues is in the cancer matrix (206). Additionally, current detection methods struggle to distinguish between different POSTN splice variants, which may possess entirely different or even opposing biological functions, potentially contributing to the data inconsistencies (34). Current research also faces notable technical limitations. The majority of studies rely on static measurements from tissue biopsies, which cannot capture the dynamic changes in POSTN expression or its real-time functional role in treatment response and disease progression. More importantly, complete inhibition of POSTN may interfere with important physiological functions, leading to side effects such as impaired wound healing, abnormal bone fibrosis or cardiac dysfunction (64). Although the role of periosteal proteins in promoting metastasis and chemotherapy resistance has been well established, it remains unclear how targeting periosteal proteins interacts with existing treatment modalities, such as chemotherapy, immunotherapy or radiotherapy, within the TME.

To overcome these challenges and drive further development in this field, future research should establish unified POSTN detection standards and conduct large-scale, multicenter prospective cohort studies to systematically assess the predictive and prognostic value of POSTN in different disease stages and treatment settings. Additionally, novel dynamic imaging technologies, such as molecular imaging probes capable of non-invasively and real-time monitoring of POSTN expression and functional activity within the body, should be actively developed. In terms of treatment strategies, the focus should be on precision interventions, including the design of inhibitors that can specifically block pathological protein interactions (such as integrin binding) without affecting physiological functions, the development of drugs targeting disease-specific isoforms and the exploration of prodrug strategies based on TME activation to minimize off-target risks to normal tissues. Finally, any clinical translation research must comprehensively assess the potential long-term effects of inhibiting POSTN on the regenerative and reparative functions of key organs such as bones, skin and the heart during the preclinical stage to ensure treatment safety. By adopting these recommendations, future research will be able to more reliably evaluate the clinical efficacy of POSTN and design safer, more effective targeted treatment strategies, ultimately bridging the gap between basic research and clinical application.

Concluding remarks

As an important matricellular protein, POSTN carries out multifaceted roles in both physiological and pathological processes, including embryonic development, allergic inflammation, fibrotic diseases and tumorigenesis (12,64). Increasing evidence indicates that POSTN can regulate various cancer hallmarks by interacting with integrins and modulating key signaling pathways such as Wnt/β-catenin, PI3K/Akt and TGF-β (27,49,51,61,74,111,166,168,180,188,207). The present review focuses on the promoting effects of POSTN on tumor growth, invasion-metastasis, angiogenesis, anti-apoptosis and immune evasion. Considering the increasingly recognized role of TME, POSTN also exerts considerable effects on niche regulation, particularly in the maintenance of CSCs, remodeling of the ECM and immune-suppressive reprogramming (102,135,140,144,208).

These findings suggest a promising therapeutic and prognostic potential for targeting POSTN in tumor management. In terms of cancer treatment, the main approaches include blocking the POSTN signaling pathway and using POSTN inhibitors. Studies have shown that Let-7f reduces angiogenesis mimicry in glioma cells by inhibiting POSTN (209,210). DNA aptamers targeting POSTN have been revealed to effectively inhibit the growth and metastasis of breast and gastric cancer in mouse models (209). POSTN can also be combined with immune checkpoint inhibitors to enhance the therapeutic efficacy of colorectal tumors (211). Moreover, selecting appropriate POSTN isoforms is important. For instance, POSTN-203 may be a more promising target for glioma because it is associated with low patient survival and contains multiple predicted human leukocyte antigen-restricted epitopes (40). POSTN can also serve as a prognostic biomarker for gastrointestinal malignancies, hepatobiliary and pancreatic cancer (212), breast cancer, ovarian cancer (20) and genitourinary cancer (59).

Key knowledge gaps still exist, including the functional heterogeneity of POSTN isoforms, the detailed mechanisms of its molecular interactions and the potential off-target effects of POSTN-targeted therapies. In summary, future research should prioritize addressing these challenges to advance POSTN-based diagnostics and therapeutics and ultimately improve the clinical outcomes of cancer and associated pathologies.

Availability of data and materials

Not applicable.

Authors' contributions

YX have made substantial contributions to the conception of the present review, wrote the main manuscript text, prepared Figs. 1 and 2, and reviewed the manuscript. LW made substantial contributions to the conception of the present review and reviewed the manuscript. Data authentication not applicable. All authors 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.

Acknowledgements

Not applicable.

Funding

The present work was supported by the Open Research Fund of Hubei Province Key Laboratory of Precision Radiation Oncology (grant no. 2024ZLJZFL003) and the Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education (grant no. 2024MZFS010), which are awarded to Dr Lufang Wang, Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.

References