The association between periostin and tumor microenvironment: a promising cancer prognostic biomarker and therapeutic target to combat tumor progression and chemoresistance

Abstract

Over the past few decades, cancer research has increasingly focused on tumor microenvironment (TME). The TME contains diverse cellular components and secreted factors, including leukocytes, endothelial cells, cancer-associated fibroblasts, and other non-cancerous cells and extracellular matrix proteins. The interactions between tumor cells and microenvironment elements are complex and unpredictable. Nonetheless, these relationships govern and control several cancer traits, including immune response, metastasis, differentiation status, cell proliferation, and resistance to cell death. In this line, Matricellular proteins, including periostin (POSTN), are increasingly recognized for their regulatory roles in the TME and cancer progression. Periostin is involved in tumor biology through matrix remodeling, invasion, and proliferation. In this review, we focused on the role of periostin as a biomarker for cancer growth and treatment resistance and a potential prognostic and therapeutic factor in cancer patients. In addition, we will discuss the periostin’s dual role as both a promoter and inhibitor of tumor growth, depending on its concentration and cellular context. Key findings indicate that low periostin levels may suppress cancer progression by preventing epithelial-to-mesenchymal transition (EMT). In contrast, high levels can enhance migration and metastasis through the activation of integrin signaling pathways. Furthermore, we will discuss the implications of targeting periostin in therapeutic strategies, particularly in light of its complex functions within the TME.

Introduction

The tumor microenvironment (TME) comprises everything around the tumor cells except the tumor cells themselves [1]. TME consists of immune cells infiltrating the tumor, extracellular matrix (ECM) proteins, and stroma cells containing growth factors, hormones, and cytokines. Tumor cells can alter the microenvironment and characteristics of the surrounding tissue [2]. Cancer cells can also be influenced by the characteristics of the tumor microenvironment. As a result, the interaction between cancer cells and the TME is a critical factor in cancer progression [3].

The ECM of the TME consists of structural proteins, such as collagens, and non-structural proteins with various functions [4]. Matricellular proteins, nonstructural extracellular matrix proteins released into the extracellular environment, are expressed at low levels in the majority of adult tissues [5]. These proteins’ interactions with cell-surface receptors facilitate communication between cells and extracellular components. Matricellular proteins also control cell growth and differentiation, crucial in maintaining normal tissue homeostasis. These proteins include osteopontin, thrombospondins, members of the CCN family (Cyr61, CCN2, CCN3), tenascins, SPARC, fibulins, and periostin (POSTN) [6].

In 1993, POSTN was first identified as a matricellular protein and has been the subject of several scientific studies since then [7]. Inflammatory diseases, fibrosis, and tumor progression are all associated with abnormal periostin expression [8]. According to recent studies, periostin expression is notably elevated in cardiac disorders and tumor tissues across most types of malignancies [9–11]. Several solid epithelial cancers are also known to upregulate periostin, and its binding to integrin receptors influences intracellular signaling pathways, directly influencing cancer characteristics [12]. Periostin is highly expressed in metastasis and can influence the size and number of metastatic lesions, indicating its significant role in the formation and alteration of cancer tissue microenvironments [13]. So, the purpose of this review is to clarify the current understanding of what periostin does regarding cancer development and metastasis. We will first examine its structure and functions within a physiological context. As well as current discoveries about periostin’s involvement in TME, we will discuss the pathological activities of periostin in the development of tumors and their metastasis. Finally, we will discuss strategies that utilize periostin or associated signaling pathways to provide new cancer diagnostic and therapeutic approaches.

Structure of periostin

Periostin, as a matricellular protein, plays an effective role in various processes such as wound healing and tissue repair, embryonic development, the organization of the extracellular matrix, and bone and tooth formation [14]. The osteoblast-specific factor-2 gene (Osf2) (Gene ID: 10631) encodes the periostin protein, which is 836 amino acids long. Alternative splicing leads to insertions and deletions in the C-terminal domain of periostin, creating periostin isoforms ranging from 83 to 93 kDa [15]. From the N-terminal to the C-terminal periostin includes the N-terminus calcium-binding domain (NTD), the EMILIN family (EMI, a small module rich in cysteine residues), the fasciclin-like domain (Fac1), and the variable hydrophilic carboxy-terminal domain (CTD), respectively [14]. The NTD domain contains a signal peptide equivalent to 22 amino acids in humans and is necessary for protein secretion. The EMI domain has a 75-amino acid length and interacts with type I collagen, fibronectin, and Notch1. The Fas1 domain binds to tenascin-c, integrin v3 and v5, cellular communication network factor 3 (CCN3), and bone morphogenetic protein-1 (BMP-1) [16]. The EMI domain is required for its ability to multimerize or form complexes with other proteins. The CTD domain has two parts: the splicing domain, which can change, and the Hbm, which is an arginine-rich heparin binding site (Fig. 1). Periostin also has two types of interactions, which include homophilic and heterophilic interactions. Homophilic interaction is for creating a dimer form, which, according to reports, can remodel the ECM, and heterophilic interaction helps it link collagen fibers by forming a meshwork structure with fibronectin and tenascin-C [17–19]. In short, periostin is a scaffold that binds collagen and BMP-1 (Bone morphogenetic protein-1). This allows BMP-1 to activate LOX (Lysyl oxidase), which then catalyzes the cross-linking of collagen molecules. In this line, periostin-null mice showed abnormalities in how collagen fibers formed in the periosteum and decreased collagen cross-linking in the skin, tendons, and heart. This finding indicates that periostin plays a vital role in collagen cross-linking through its ability to multimerize and form a network with fibronectin, tenascin-C, and other proteins [20–22].

Fig. 1.

Structures of the periostin gene and protein. (A) Periostin has a single sequence, the EMI domain, the four FAS-1 domains, and a variable domain (VD) with nine (15–23) exons. The combination of exons 15–23 results in four periostin isoforms that have been sequenced and elucidated. A total of 23 exons were present in periostin. The gene is located at 13q13.3 in humans. Exons at the end of the gene code for proteins. Several functions of the periostin are mediated by its N-terminal region. Extracellular matrix molecular entities are bound to the C-terminal, which regulates its general organization. (B) three-dimensional modeling of the four fasciclin domains of periostin. The predicted tridimensional structural model of human periostin is colored according to domains FAS1^І, FAS1^II, FAS1^III, and FAS1^IV. The EMI domain is depicted in brown, and the CTD is highlighted in brown. Created by BioRender. Farnoosh, F. (2024) https://BioRender.com/r08v107

Periostin’s multifaceted role in tumor progression and microenvironment modulation

Periostin plays different roles depending on its location within tissues. Studies have found differences in periostin localization between healthy and diseased states [23, 24]. Periostin is mostly located in the epidermis and keratinocyte nuclei in healthy skin. On the other hand, periostin is mostly found in the extracellular matrix and massive fibrils that encircle cells in the dermis that have undergone remodeling. Different localization patterns are also seen in periostin isoforms. Isomers devoid of exons 17 and 21 are detected in the heart tissue, periosteum, and periodontal ligament following a myocardial infarction. Periostin location is also changed in cancerous tissues [24]. Periostin was found in the cytoplasm of tumor cells, fibroblasts, and the extracellular matrix of the tumor stroma in a study of thirty non-small cell lung cancer samples [25]. In many cancers, periostin is primarily found in the tumor stroma but is also detected in epithelial tumor cells and both epithelial and stromal cells [26, 27]. Mostly, periostin has been detected in the stroma of nasopharyngeal carcinoma, ductal carcinoma in situ, and inflammatory breast cancer [28]. Some studies have found that periostin can have a biphasic or dose-dependent effect on cancer cells. At low concentrations, periostin may suppress cancer progression, while at high concentrations, it can promote cancer [29]. For example, 150 ng/ml of periostin in pancreatic cancer cells can prevent EMT, decrease cell migration in vitro, and suppress metastasis in vivo. This study suggests that, at low levels, periostin inhibits cancer progression. However, at high periostin levels of 1 µg/ml, pancreatic cancer cell migration is stimulated through the activation of the Akt pathway [29]. This indicates that periostin can promote cancer cell migration and metastasis at high concentrations. Also, several lung cancer studies have unexpectedly found that periostin is downregulated in cancer tissues compared to normal lung tissues, suggesting that low periostin levels may contribute to lung cancer development [30, 31]. Based on these findings and other research, periostin derived from different cell types, like cancer cells versus stromal cells, may play distinct roles in promoting or inhibiting tumor development [32]. This is likely because periostin from different sources binds to various integrin receptors on cells, and these different integrin receptors activate distinct signaling pathways that either promote or suppress cancer [13]. In other words, periostin from cancer cells may bind to integrins that activate pro-cancer signaling, while periostin from stromal cells may bind to integrins that inhibit cancer signaling [33]. This could explain why periostin has both tumor-promoting and tumor-suppressing effects, depending on its source and concentration. So, the concept of a “periostin switch” refers to the changing functions of periostin over time during tissue development and repair. Early after periostin is expressed, it appears to act as a positive regulator of collagen synthesis. However, periostin function shifts to promoting collagen cross-linking. This later role depends on the cleavage of periostin’s C-terminal domain. This functional switch from collagen synthesis to collagen cross-linking is thought to be an essential part of how periostin regulates extracellular matrix remodeling [13]. Periostin binds to integrins on the surface of cancer cells, activating the Akt/PKB and FAK signaling pathways. So, periostin can increase angiogenesis, invasion, metastasis, and cell survival, thus promoting cancer progression (Fig. 2). For example, Tai et al. found that treating colorectal cancer cells with periostin significantly increased their proliferation rate, suggesting that periostin can promote colorectal cancer cell growth [34]. However, another group of researchers reported that periostin overexpression did not directly increase cancer cell proliferation. Instead, they found that periostin promotes angiogenesis by upregulating VEGF receptor 2 (VEGFR2) expression on endothelial cells via integrin αvβ3 and FAK signaling. Research demonstrated that a neutralizing monoclonal antibody against periostin prevented anchorage-independent growth and decreased survival in cancer cell lines that produced periostin [35]. The antibody’s neutralizing effects also suppressed the migration and invasion abilities of these cancer cells. This suggests that periostin supports tumor growth and metastasis, and targeting it with a monoclonal antibody may help block these processes and cancer progression. Periostin also increases tumor angiogenesis and decreases tumor cell apoptosis in epithelial ovarian cancer (EOC). In EOC, recombinant POSTN also stimulates Akt phosphorylation to increase resistance to paclitaxel. Studies have shown that molecular actions in the AKT pathway represent an essential determinant of chemosensitivity to platinum in EOC [31, 36]. In general, the effect of periostin on cancer cell proliferation depends on the specific cell type. Periostin has also increased cancer cell migration, invasion, and adhesion by 2 to 9-fold through cross-talk between the integrin and epidermal growth factor receptor (EGFR) signaling pathways and further contributes to periostin’s pro-tumorigenic effects [37]. For example, in the microenvironment of pancreatic ductal adenocarcinoma (PDAC), secreted periostin can bind to the EGFR, activating various downstream signaling transduction pathways such as Akt and Erk-c-Myc signaling [38].

Fig. 2.

Overview of the signaling pathways involved in periostin-induced metastasis. Through cross-talk between integrin and EGFR, periostin activates PI3K/Akt signaling pathways, increasing MMP-9, vimentin, fibronectin, and N-cadherin. So it increases angiogenesis and metastasis. Periostin activates the ß-catenin dependent pathway by inducing wnt binding to its receptors, resulting in CSC self-renewal and metastasis. By binding to its receptor, periostin activates the NF-kβ pathway, which leads to the transcription of IL-6 and IL-8, ultimately leading to the self-renewal and metastasis of cscs. Through periostin’s interaction with BMP-1, collagen cross-linking, and ECM stiffness are enhanced, leading to metastasis. Created by BioRender. Farnoosh, F. (2024) https://BioRender.com/l63q681

The proliferation, metastasis, and survival of pancreatic cancer cells can all be enhanced by activating these signaling pathways. Note that bladder cancer does not exhibit periostin overexpression, which is linked to increased invasiveness in the majority of malignancies [39]. Some studies have found that periostin is overexpressed in bladder cancer and linked to a poor prognosis, yet it does not promote invasiveness. Periostin affects EMT (epithelial-mesenchymal transition) and cell invasion differently in prostate cancer versus bladder cancer [40].

In prostate cancer, periostin increases AKT phosphorylation, upregulating the EMT promoter Snail and downregulating E-cadherin. This leads to increased cell invasion [41]. However, periostin suppresses AKT phosphorylation in bladder cancer, downregulating the EMT promoter Twist and upregulating E-cadherin. This decreases cell invasion. Similarly, in gastric cancer, epithelial-derived periostin acts as a tumor suppressor. It stabilizes the tumor suppressor proteins p53 and E-cadherin, decreasing EMT and invasion [42]. However, Yang Liu et al. found that human pancreatic ductal adenocarcinoma (PDAC) tissue samples had higher levels of periostin in their stroma when compared to nearby normal tissues. This finding raises the possibility that periostin might be a helpful biomarker for PDAC diagnosis. They also demonstrated that in PDAC patients, periostin was a predictor of advanced clinical stage and shorter overall survival. Moreover, periostin knockdown reduced the development and progression of tumors in subcutaneous xenografts, corroborating periostin’s involvement in in vivo carcinogenesis [38].

Periostin as a prognostic and therapeutic factor in cancer patients

Several studies have been performed on periostin overexpression in cancer epithelial cells and tumor stroma related to a more aggressive tumor, weak prognosis, or advanced stage, as well as shorter overall survival in different cancers [40, 43].

. Several studies have proven this evidence in several cancer types such as lung cancer, colorectal cancer (CRC), ovarian cancer, pancreatic cancer, etc [31, 44]. Tischler et al. represented the robust periostin expression in tumor stroma related to shorter progression-free survival [30]. It was also revealed that high periostin expression in tumor stroma was associated with the stage of the tumor, Gleason score, and the malignancy degree [27]. Similarly, Ben et al. found a weak prognosis associated with higher periostin expression in cancer epithelial and stroma cells than in the nearby tissue [45]. It was also revealed that higher periostin expression in tumor stroma was related to the survival rate and pathological grade in pancreatic ductal adenocarcinoma (PDAC) patients [46]. Moreover, OSCC invasion and angiogenesis were promoted by periostin overexpression. Compared to periostin-negative tumor tissues, there is a greater blood vessel density for periostin-positive tumor tissues. The capillary formation is also enhanced by recombinant periostin in a concentration-based manner in OSCC cells, according to an in vitro examination [47]. In tumor stroma, high periostin expression is related to reduced patient survival in prostate and pancreatic cancer. Thus, it can be utilized as a prognostic biomarker. The association between the expression of periostin in cancer stem cells and the patient’s prognosis was also investigated by Lambert et al. [48]. They found that higher periostin expression in these cells was related to the decreased relapse-free survival in basal-like type rather than the luminal breast cancers [49]. According to Bao et al., in liver metastasis, periostin mRNA expression levels were higher compared to the primary tumor taken from the same patients [37]. Wu et al. describing a multivariate analysis, revealed that liver metastasis was related to the lymph node metastasis, histological type, periostin levels, and TNM stage [50]. According to Jang et al., higher periostin expression in hepatocellular carcinoma was related to microvascular invasion. Moreover, progressive-stage disease and higher periostin expression were associated with lower overall survival rates. Thus, an association is represented between weak prognosis and periostin expression [51]. Utispan et al. indicated that in intrahepatic cholangiocarcinoma, periostin is over-expressed by CAFs rather than immune infiltrating cells or cancer cells. Shorter survival rates were found for patients with higher periostin levels [52]. In contrast, periostin expression is downregulated in bladder cancer than normal tissue, unlike most tumors [53]. Immunohistochemically, robust staining of periostin was represented by analysis in the normal bladder stroma, though it was attenuated generally in bladder cancer tissues. Outstandingly, there was an inverse correlation between periostin downregulation and tumor grade. Therefore, only periostin was expressed in only 33% of grade III bladder cancer, while its expression was found in 100% of normal bladder tissues. The canonical isoform of periostin was expressed in normal bladder tissues though others spliced mRNAs alternatively. However, the canonical periostin isoform is not expressed in bladder cancer tissues and urine, with only some alternatively spliced isoforms. Fascinatingly, tumor suppressor activity was not represented by the alternative isoforms expressed in cancer tissues, unlike the canonical isoform. Therefore, a relation is indicated between canonical periostin and bladder cancer development revealing that periostin can be a potential urinary biomarker for the progression of cancer [53].

Several research has examined whether POSTN levels in serum are correlated with cancer prognosis as periostin levels in tumor tissues are related to prognosis in various malignancies [31, 39].

Serum samples from individuals with certain malignant tumors showed elevated periostin levels, indicating that this biomarker may be useful for both diagnosis and survival prediction [54]. According to this line, some cancer patients had blood levels of periostin that were greater than normal, suggesting that this biomarker might be useful for both diagnosis and prognosis. Nuzzo et al. found that in certain individuals who were not getting adjuvant systemic therapy, there was a connection between higher blood levels of periostin and mortality specific to breast cancer. Additionally, Nuzzo et al. investigated the location of periostin in tumor tissues and showed that it is present in peritumoral regions, tumor stroma, and cancer epithelial cells [55]. In the stromal component, higher periostin expression was related to shorter survival [56]. However, in cancer epithelial cells, lower periostin expression was correlated significantly with less progression-free survival. The worsened prognosis was indicated in patients with higher periostin levels in the stroma component and lower levels in cancer epithelial cells [56]. Furthermore, serum periostin was also found in initial breast cancer before surgery, and worse long-term survival was predicted by higher serum baseline levels for definite patient subgroups [57]. In 296 NSCLC patients, serum periostin levels were also considerably higher than in healthy controls or benign lung disease patients [58]. Moreover, a correlation was also found between serum periostin levels and chemotherapy response and bone metastases in the patients [59]. Sasaki et al. showed that breast cancer patients with bone metastases had higher serum levels of periostin than those without metastases. This suggests that serum periostin levels could be a valuable biomarker to identify patients at higher risk of bone metastasis [60]. However, there was no association between periostin serum levels and other predictive factors such as clinical stage and lymph node metastasis. Stromal periostin is also an effective biomarker for predicting colorectal cancer (CRC) metastasis [61]. Periostin promotes CRC growth and increases metastatic potential by activating the PI3K/Akt signaling pathway [61]. High levels of stromal periostin secretion are an unfavorable prognostic factor for CRC patients. Therefore, stromal periostin level is a crucial predictive biomarker for CRC, and targeting periostin-mediated signaling pathways could be a viable therapeutic approach for metastatic CRC [61]. As in the study conducted by Deng et al. on patients with CRC, it was shown that serum levels of periostin were significantly higher in affected individuals than in healthy individuals, and patients with lower serum periostin had lengthier overall survival [61]. Fujimoto et al. conducted a study to examine the serum levels of periostin in patients diagnosed with intrahepatic cholangiocarcinoma [62]. The findings revealed that the levels of periostin were significantly elevated in these patients when compared to normal controls, as well as those with liver cirrhosis, hepatocellular carcinoma, and other malignancies [63]. In another study conducted by Park et al., the role of periostin in the prognosis and recurrence of tongue cancer has been investigated due to its association with head and neck squamous cell carcinoma (HNSCC) [64]. The clinical findings of this study have shown a significant relationship between the high expression of periostin and cancer recurrence. Further experiments showed that periostin inhibited colony formation, migration, invasion, and wound healing, promoting tumor progression in vitro and in vivo. Therefore, larger serum periostin levels were related to overall survival (OS) and weaker progression-free survival (PFS), which indicated serum periostin levels as an independent prognostic marker [58]. These results have also demonstrated that targeting periostin may be promising as a therapeutic strategy for cancer therapy/treatment. Table 1 represents the relationship between clinicopathological parameters periostin expression and survival.

Table 1.

The association between clinicopathological parameters and Periostin expression and survival

Cancer	Higher expression in	Association with	Ref
Prostate cancer	Stroma and epithelial	OS (weak prognosis) High PN stromal expression is associated with lower survival, and low PN epithelial expression relates to decreased PSA-free survival. PN stromal expression has a weak connection to Gleason scores, while PN epithelial expression correlates significantly with extra-prostatic extension.	[65]
	Stroma	High levels of PN expression in the stroma are significantly associated with higher Gleason scores.	[30]
	Stroma and epithelial	High levels of PN expression in the stroma are significantly associated with the degree of malignancy, as indicated by the Gleason score. In contrast, PN epithelial expression is elevated in the early stages of prostate cancer (Gleason scores 6–7) but does not increase in the more advanced stages of the disease.	[66]
	Stroma	High levels of PN expression in the stroma are significantly linked to poor prognosis, while there is no statistically significant relationship between epithelial PN expression and overall survival (OS).	[67]
Lung cancer	Stroma and epithelial	High levels of PN expression are associated with male gender, advanced stage, higher pT category, and larger tumor size in both stromal and epithelial tissues. However, tumor relapse is linked only to stromal expression. Additionally, high stromal PN expression is inversely correlated with progression-free survival (PFS) and serves as a prognostic factor for reduced PFS.	[68]
	Stroma	High levels of PN expression are inversely associated with overall survival (OS), but PN does not act as an independent prognostic factor.	[69]
Pancreatic cancer	strong positive in the neoplastic stroma/epithelium	High levels of PN expression in the neoplastic stroma are significantly correlated with the depth of invasion and the presence of lymph node metastasis. PN expression in either the stroma or epithelium is associated with poor survival outcomes.	[46]
Ovarian cancer	Cancer epithelial and stroma cells	Patients with overexpression of PN in the stroma experienced significantly shorter overall survival (OS) and disease-free survival (DFS) compared to those with low PN expression. This overexpression is also linked to poor prognosis, platinum resistance, a higher incidence of advanced FIGO stage, and an increased rate of tumor recurrence after initial treatment.
	Tissue	High levels of PN expression are significantly correlated with advanced clinical stages (III/IV) and cancer recurrence.	[46]
Breast cancer	epithelial	High levels of epithelial PN expression are associated with reduced disease-free survival and overall survival.	[36]
	Cancer-associated fibroblasts	High levels of PN expression in cancer-associated fibroblasts (CAFs) are correlated with tumor grade and shorter overall survival.	[70]
Colorectal cancer	Stroma	High levels of PN expression in tumor stroma are significantly associated with tumor location in the proximal colon, undifferentiated histology, infiltrative growth patterns, tumor budding, luminal necrosis, and higher TNM stage. Additionally, high stromal PN expression serves as an independent prognostic factor for poor 5-year cancer-specific survival and 5-year progression-free survival (PFS).	[56]
	Cancer epithelial cells	A high level of PN expression is linked to metastasis.	[28]
Hepatocellular carcinoma	Cancer epithelial cells	High levels of PN epithelial expression are significantly associated with higher tumor grade, reduced overall survival (OS), younger age at diagnosis, female gender, and HBV infection. Additionally, PN expression is independent of pT level, differentiation grade, and proliferation rate in primary biliary ductal carcinoma (BDC).	[71]
	Tissue	PN levels were higher in patients with multiple tumors, positive microvascular invasion, and advanced-stage disease. High PN expression is significantly inversely associated with overall survival.	[50]
Bladder cancer	Stroma	Stromal PN mRNA levels were significantly elevated in muscle-invasive bladder cancer (MIBC) tissue compared to non-muscle-invasive bladder cancer (NMIBC) and normal tissue, with MIBC PN levels being 70 times higher than in healthy controls. Epithelial PN expression in MIBC tissues is linked to reduced progression-free survival and disease-specific survival, indicating poor clinical outcomes. Patients with PN-positive MIBC cells face a significantly higher risk of tumor development and disease-specific mortality. Additionally, mild to high (2+/3+) levels of PN expression correlate significantly with disease progression in patients with NMIBC.	[72]
	Tissue	Downregulation of PN mRNA is significantly correlated with higher tumor grade and stage. PN mRNA expression is more prevalent in bladder cancers at a low stage (pTa) with 66.6% (12 out of 18 cases) compared to only 33.3% (5 out of 15 cases) in those with a high stage (pT1–3).	[51]
Osteosarcoma	Tissue	High levels of PN expression are associated with histological subtype, Enneking stage, tumor size, VEGF expression, and increased microvessel density. Patients with PN-positive expression experience significantly shorter overall survival (OS) and disease-free survival (DFS) compared to those with PN-negative expression. Moreover, PN expression, along with histological subtype, Enneking stage, and tumor size, serves as an independent prognostic factor for OS and DFS.	[40]

Abbreviation: pgr: Progesterone receptor; CLIA: Chemiluminescence immunoassay; MIBC: Muscle-invasive bladder cancer; DFS: Disease-free survival; pca: prostate cancer; IHC: Immunohistochemistry; WB: Western blotting; NMIBC: Non-muscle-invasive bladder cancer; MA: Microarray analysis; ELISA: enzyme-linked immunosorbent assay; NB: Northern blot; IB: Immunoblot

Periostin and tumor microenvironments (TME)

TME refers to the niche where tumor cells grow and reside. It contains various components that can influence tumor progression, including growth factors and cytokines, ECM, stromal cells like fibroblasts, immune cells, endothelial cells, and tumor cells [73]. As a secreted protein, Michaylira, C. Z., et al. suggest that the induction of periostin may alter the TME by accumulating in the surrounding stromal tissue [74]. This could facilitate invasion through remodeling of the ECM. To do this, periostin may control the formation of type I collagen fibrils, act as a link between tenascin C and the ECM, and interact with αVβ3 integrins [37]. Furthermore, periostin could promote tumor cell survival within the ECM by activating the AKT/PI3K pathway. In addition to ECM remodeling, periostin may be involved in cancer metastasis through several mechanisms, including, premetastatic niche formation, cancer stem cell niche formation, perivascular niche, and fibrotic microenvironment establishment [14]. In addition, periostin regulates key metastatic processes like EMT, an essential step in the metastatic cascade, and cancer cell motility, survival, angiogenesis, and stemness, which enable metastasis [75].

Cancer stem cell niche

Cancer stem cells (CSCs) are a subpopulation of tumor cells that can self-renew and differentiate, driving tumor initiation, progression, and metastasis [76]. There is a close interaction between CSCs and the metastatic niche they inhabit. Periostin plays an essential role in forming this cancer stem cell niche [77]. For example, in breast cancer, cancer stem cell-derived TGF-β can induce cancer-associated fibroblasts to secrete periostin into the cancer stem cell niche. Periostin then recruits Wnt signaling in cancer stem cells, which promotes stem cell-like traits and a mesenchymal phenotype. This enhances breast tumor growth and lung metastasis [78]. On the other hand, periostin secreted by breast tumor cells can maintain breast cancer stem cells by regulating IL-6 and IL-8 cytokines [48]. In acute myeloid leukemia, CSCs express periostin and its receptor integrin in secondary target tissues, indicating periostin’s autocrine and paracrine effects on the CSC’s behavior, like invasion and metastasis [48].

In glioblastomas, periostin secreted by glioma stem cells recruits M2 tumor-associated macrophages (TAMs) from the bloodstream to the TME. This occurs through the activation of the αvβ3 integrin signaling pathway. M2 TAMs are immunosuppressive and promote tumor progression. They form part of the supportive niche for glioma stem cells. So, in glioblastomas, periostin secreted by glioma stem cells recruits M2 macrophages to the TME. These M2 macrophages then help form a supportive niche for the glioma stem cells. Periostin can also influence CSC maintenance by activating the periostin-integrin signaling axis. It promotes cancer stem cell-supporting niche formation and thereby maintains CSCs [79].

The perivascular niche

The perivascular microenvironment around blood vessels is essential for tumors. It allows tumor cells to survive in the vasculature of primary and distant organs during metastasis and provides a niche for disseminated tumor cells to form secondary metastases after a latent period [80]. The data show that established microvessels provide inhibitory cues that maintain the dormancy of disseminated tumor cells. However, sprouting neovasculature provides stimuli like periostin and TGF-β1 that promote the metastatic outgrowth of disseminated breast cancer cells [81].

In this line, periostin secreted by endothelial tip cells was identified as one of the tumor-promoting factors in the perivascular microenvironment [82]. Periostin acts as a pro-angiogenic factor by binding integrin αvβ3 and upregulating the VEGF receptor Flk-1/KDR via FAK signaling, promoting tumor angiogenesis [83]. The perivascular niche around blood vessels has different properties depending on the vascular maturity. Endothelial cells in mature vessels express high levels of thrombospondin-1 (TSP-1) and other factors [84]. This perivascular niche maintains breast cancer cell dormancy. Endothelial cells in new vessels produce periostin, tenascin C, fibronectin, TGF-β, and versican. This establishes a different perivascular niche that accelerates tumor outgrowth. So, the functional state and secretome of the perivascular dependent on vascular maturity, determines whether it maintains dormancy or accelerates the outgrowth of disseminated tumor cells [85].

Pre-metastatic niche

Research suggests that pre-metastatic niches existed in distant organs before the arrival of metastatic tumor cells [86]. These niches prepare the organs to allow disseminated tumor cell colonization and outgrowth. Several types of cells are involved in the formation of pre-metastatic sites; two critical types of them include: (1) bone marrow-derived VEGFR1-positive hematopoietic progenitor cells that are recruited to future metastasis sites, and (2) Myeloid-derived suppressor cells (MDSCs) accumulate in pre-metastatic niches that promote tumor metastatic outgrowth [56]. These cells help establish a supportive microenvironment that primes distant organs for metastasis. They remodel the ECM, stimulate angiogenesis, suppress immune responses, and secrete factors that attract tumor cells [87]. Specifically, periostin recruits myeloid-derived suppressor cells (MDSCs) to the pre-metastatic niche in the lungs during breast cancer metastasis. It activates the ERK, AKT, and STAT3 signaling pathways in the MDSCs. It should be noted that MDSCs from the periostin-knockout mouse lungs showed significantly reduced levels of immunosuppressive factors like ADAM17, VEGF, TGF-β3, and iNOS [88]. Periostin secreted by cancer-associated fibroblasts (CAFs) can also contribute to forming the premetastatic niche that facilitates lung metastasis of breast cancer [89].

Specifically, CAF-derived periostin promotes the formation of the premetastatic niche in the lungs. This prepares the lung microenvironment to support the colonization and growth of metastatic breast cancer cells [90]. Another study found that periostin is highly expressed in bleomycin-induced lung fibrosis. This lung fibrosis greatly enhances lung metastatic colonization by B16 melanoma cells. These findings suggest that secreted periostin from CAFs and other cell types within lung fibrosis may establish a premetastatic niche in the lungs [91]. This niche supports the colonization and outgrowth of metastatic tumor cells from distinct primary cancers like breast cancer and melanoma. In a mouse model of breast cancer metastasis, periostin was required to form an immunosuppressive pre-metastatic niche in the lungs [92]. Another study found that periostin is a critical component of the pre-metastatic niche that promotes the metastasis of remotely transplanted melanoma cells to wound sites [93].

Fibrotic microenvironments

Periostin has a role in the development of fibrotic microenvironments, which facilitate the growth of tumors. For instance, activated pancreatic stellate cells in pancreatic cancer alter the TME by producing more TGF-β, collagen, periostin, and fibronectin [49]. Periostin plays a part in the formation of fibrotic microenvironments, which promote tumor growth. For example, increased production of TGF-β, collagen, periostin, and fibronectin by activated pancreatic stellate cells in pancreatic cancer modifies the TME [94].

Periostin and cancer progression

As mentioned above, periostin acts in fibrosis, cancer, as well as inflammatory diseases like infarcted arthritis, myocardium, asthma, and atherosclerosis. Dysregulating the periostin expression in various cancers represents its key role in the progression and development of cancer. Therefore, angiogenesis, invasion, metastasis, and cell survival are increased [95]. In the following sections, the contribution of periostin to cancer angiogenesis, invasion, and metastasis will be mentioned (Fig. 3).

Fig. 3.

Possible roles for periostin in tumorigenesis. Periostin could be involved in the transformation of normal cells into metastatic tumors by preventing apoptosis. It could also promote cell proliferation, migration, EMT, and invasion. Created by BioRender. Farnoosh, F. (2024) https://BioRender.com

The role of Periostin in cancer invasion and metastasis via EMT induction

Periostin has a role in the invasion and migration of cancer cells by controlling important processes including EMT [31]. EMT is a physiological process that was first detected in embryonic development and subsequently shown to also occur during tumor growth [96]. It involves the transformation of epithelial cells into cells with a mesenchymal phenotype. This process is especially significant in epithelial cancers, where normal epithelial cells, which are oriented along their apical-basal axis and are strongly interconnected, undergo a phenotypic change characterized by the loss of apical-basal polarity and the acquisition of migratory traits that enhance mobility and invasion [97]. The EMT program is controlled by EMT transcription factors (i.e., Snail, Twist, and Zeb families) and involves the coordinated upregulation and downregulation of several ECM and cell-cell adhesion genes [98].

Several studies have shown that periostin promotes EMT in cancer cells. For instance, according to Hu et al., EMT was induced by recombinant periostin in CL1-0 and A549 lung cancer cells [99]. Upregulation of N-cadherin, Vimentin, Twist, and Snail genes was induced by POSTN, whereas downregulation of E-cadherin was observed [100]. Through activating ERK and p38 pathways, POSTN downregulated miR-381 expression, which targets Twist and Snail mRNAs. A POSTN-induced increase in EMT-associated factors was followed by activation of Akt and GSK-3β pathways. As a result, TGF-β increased POSTN and Twist expression, suggesting that POSTN is a mediator of TGF-β-induced EMT [101]. Kim et al. indicated that EMT was induced, and invasiveness was increased by periostin in prostate cancer cell lines through downregulating E-cadherin by Snail and enhanced phosphorylation of Akt [102]. In bladder cancer cells, POSTN increased E-cadherin expression while suppressing cell invasiveness, whereas in prostate cancer cells, the opposite occurred, suggesting tumor cell-specific effects of POSTN [102].

The role of Periostin in tumor angiogenesis

These days, it is indicated that the tumor’s unrestricted growth is based on angiogenesis. It has been evidenced that angiogenic signaling cascades are promoted by several molecules in endothelial cells [103]. VEGF acting through its membrane tyrosine kinase receptors, receptor 2 (Flk-1/KDR) and VEGF receptor 1 (Flt-1) are among the strong angiogenic molecules [104]. Angiogenic signaling pathways are activated by several molecules in human microvascular endothelial cells [105]. Periostin was found as a potent pro-angiogenic factor as well as a powerful and new angiogenic factor for tumor growth [95]. Angiogenesis is promoted by periostin in tumor metastases, thus enabling the proliferation and survival of tumor cells after colonizing distant tissues [82]. Secreting periostin sends signals through the cell adhesion molecules integrins αvβ3 and αvβ5. Here, the PKB/AKT and FAK/Src signaling pathways are activated by periostin resulting in enhanced angiogenesis, improved metastatic ability and invasiveness, and reduced apoptosis. Angiogenesis is induced by periostin partly by upregulating VEGF receptor 2 (Flk-1/KDR) on endothelial cells via integrin signaling. Flk-1/KDR and VEGF are also included in inducing angiogenesis development during solid tumors. In human colon cancer metastases and primary tumors, periostin is expressed differentially [106]. Moreover, a higher periostin expression level is related to metastatic colon tumor cells. Elevated periostin expression was also recognized in nude mice-inoculated colon cancer cells. Moreover, liver metastatic growth is promoted by periostin, indicating that periostin has a key role in the late stages of cancer progression [37]. In this regard, tumor cells-secreted periostin induces angiogenesis via paracrine signaling over metastases. It is also indicated that periostin is a hypoxia-response gene mediating cross-talk between endothelial cells and cancer cells under hypoxic circumstances, at least through the regulation of VEGF expression partially. Tumor angiogenesis is promoted by breast cancer cell lines overexpressing periostin in vivo by VEGF receptor Flk-1/KDR upregulation in endothelial cells by activating FAK signaling via integrin-αvβ3. Though a growth advantage may be conferred by periostin to breast tumors in vivo by changing the microenvironment via angiogenesis promotion, a growth disadvantage may be imposed by its overexpression for the tumor cells’ growth in culture [107]. Furthermore, in head and neck cancer, periostin expression is correlated with VEGF-C expression in tumor serum and tissue. Colorectal cancer is an instance of metastatic growth significantly increased by periostin through promoting human endothelial cell survival and induction of angiogenesis [61].

Periostin and chemoresistance

Several studies have shown that periostin may have a significant impact on treatment resistance in some solid tumors [25, 106]. Research has highlighted that periostin contributes to chemotherapy resistance [108]. The Western blot analysis of SW480 and HT-29 colon cancer cells demonstrates that chemotherapy medicines upregulate the expression of periostin [109]. Suppressing periostin enhances the susceptibility of colon cancer cells to drug-induced apoptosis. When periostin siRNAs are present, they greatly increase the cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) [37]. These are enzymes that cause apoptosis by changing the potential of the mitochondrial membrane. Consequently, cancer cells become more sensitive to chemotherapeutic treatments [110]. A platinum/taxane-based regimen is usually the first step in treating ovarian cancer. Researchers are currently developing biomarkers for predicting platinum response following resistance to platinum therapy [111]. The immunohistochemistry research revealed that periostin is excessively expressed in the malignant stroma of individuals with epithelial ovarian carcinoma (EOC) [112]. According to the mentioned evidence, we will discuss the role of periostin in chemoresistance via signaling pathways, EMT processes, and autophagy.

Association between signaling pathways stimulated by Periostin and chemoresistance

The research done on colon cancer cells has shown that the PI3K/AKT/survivin pathway plays a crucial role in activating chemoresistance [113]. Periostin overexpression induces phosphorylation of AKT at serine 473 and triggers activation of the PI3K/AKT pathway, producing survivin in cancer cells [114]. Survivin functions as an inhibitor of caspase-9, displaying anti-apoptotic properties and playing a role in the development of chemoresistance [115]. Experiments on SW480 and HT-29 cells treated with oxaliplatin or 5-FU have shown that decreasing the amount of periostin leads to a significant decrease in survivin expression at the protein level [116]. Additionally, the AKT/PKB pathway is involved in conferring chemical resistance in samples of two distinct kinds of cancer [117]. Periostin enhances the viability of colon cancer cells by stimulating the AKT/PKB pathway [35]. In another case, the condition of low oxygen levels, known as hypoxia, causes an increase in the production of periostin in non-small cell lung cancer. This periostin then promotes the activation of the AKT/PKB pathway [118]. Indeed, when cancer cells are exposed to the stressful effects of chemotherapy, they use the mechanism of upregulating periostin as a means of enhancing their chances of survival. Conversely, the increased expression of αvβ3 integrin and α6β4 integrin is closely associated with the progression of angiogenesis and the spread of tumors [119].

Under conditions of hypoxia-induced cell death in colon cancer, periostin activates the PI3K/AKT pathway via αvβ3 integrin to enhance cell survival. Periostin also activates epidermal growth factor receptor signaling pathways by binding to αvβ3, αvβ5, and α6β4 integrins, promoting AKT/PKB and focal adhesion kinase (FAK)-mediated signaling pathways that result in chemotherapy resistance by inhibiting apoptosis [119]. Hypoxic stress contributes to chemoresistance in cancer cells, with hypoxia-inducible factor-1 alpha (HIF-1α) playing a key role in inducing genes involved in the hypoxic response [120]. Periostin expression increases transcriptional activity dependent on HIF-1α, enhancing periostin expression reciprocally. HIF-1α targets anti-apoptotic proteins like Survivin, Mcl-1, and Bcl-xL, aiding cell adaptation to hypoxic conditions. During hypoxia, periostin upregulation promotes cell survival genes and resistance to arsenic trioxide (ATO) in hepatocellular carcinomas (HCCs) [121]. In non-small cell lung cancer (NSCLC), periostin also inhibits the induction of cleaved caspase-3 and activates Stat3/survivin signaling, resulting in resistance to cisplatin (CDDP)--based chemotherapy [25].

Association between EMT and Periostin in chemoresistance

According to the findings, autophagy positively regulates EMT in some cases and negatively regulates it in others [122]. Probably, various factors play a role in determining the type of this relationship. Observations suggest that periostin reduces autophagy through ITG α5β1 or α6β4, by activating the AKT pathway to induce EMT [123]. It should be noted that integrin alpha 5 beta 1 (ITG α5β1) is a kind of integrin protein that is present on the surface of cells. The ITG α5β1 integrin is essential for many biological processes, such as cell migration, proliferation, and differentiation, and it binds particularly to fibronectin, a vital part of the extracellular matrix. It plays a key role in tissue repair, wound healing, and development [124]. The integrin protein known as α6β4 is made up of two subunits: beta 4 (β4) and alpha 6 (α6). Primarily present in epithelial cells, this integrin is essential for cell attachment to the extracellular matrix, especially to laminin, a key building block of the basement membrane [124].

Autophagy-mediated EMT is an important pathway in predicting periostin behavior. It may be concluded that EMT enhancement is a priority for periostin and according to the cell conditions, periostin is trying to increase EMT either by suppression of autophagy or induction of autophagy [119]. Also, the periostin effect in inducing or inhibiting autophagy can be influenced by the type of target cells, the cancer stage, or the dual behavior of autophagy in reducing or increasing the cancer cell’s growth.

Periostin is a protein that is crucial in chemoresistance in various cancers, including triple-negative breast cancer (TNBC) [47]. It is associated with EMT, a process linked to chemoresistance and poor prognosis in TNBC [47]. Studies have shown that periostin induction is significantly correlated with EMT gene signatures and poor outcomes in breast cancer patients, particularly those with TNBC [108, 125].

Periostin promotes chemoresistance by inducing EMT, increasing cancer cell stemness, and activating specific pathways. In TNBC xenografts, chemotherapy can upregulate periostin expression, leading to the expansion of mesenchymal tumor cells and increased invasion in residual tumors [47]. Blocking periostin has shown promise in overcoming chemoresistance by restricting the expansion of mesenchymal tumor subpopulations [126]. Understanding the role of periostin in cancer progression and its interaction with other molecules is crucial for developing effective treatments targeting chemoresistance.

Increased expression of periostin is linked to increased expression of membrane-type metalloproteases, or MT-MMPs, after chemotherapy. MT-MMPs cause the basement membrane to undergo proteolysis and encourage the growth of tumor cells with a mesenchymal character. Periostin increases the expression of MMPs such as MMP-9, MMP-10, and MMP-13 [108]. MMPs degrade the ECM. On the other hand, tumor cells come into contact with ECM proteins after the basement membrane is destroyed, and this interaction is crucial for the development of chemical resistance [127]. Mesenchymal cell growth following chemotherapy is inhibited by periostin deletion [128]. Researchers reported a decrease in the expression of genes associated with the mesenchymal phenotype in a study where they utilized shRNA to eradicate periostin in tumor cells. Additionally, the repressed periostin expression led to an elevated epithelial cell population, as reported by immunohistochemical staining [99]. We now know with certainty that periostin damages the basement membrane, which in turn contributes to the developing mesenchymal phenotype. The results of laminin-5 staining showed that the basement membrane of periostin-depleted tumors remained intact and the expression of MT1-MMP was reduced [108]. In combination with periostin removal, chemotherapy-induced effects were reversed in many cases. MMP-9 and MT1-MMP expression dropped along with the mesenchymal cell population [108].

Notch signaling is one of the mechanisms involved in the regulation of EMT. Research conducted on the development of heart tissue showed that the absence of periostin led to the inhibition of Notch1 signaling, thereby validating the involvement of periostin in the induction of EMT. Notch signaling has a role in both tissue growth and programmed cell death. The binding of the ligand initiates a series of proteolytic cleavages, resulting in the activation of SNAIL and Twist transcription factors.

Association between EMT regulating mRNAs/LncRNAs and Periostin in chemoresistance

MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression by binding to mRNA, impacting carcinogenesis [129]. In hepatocellular carcinoma (HCC), low miR-876 levels suggest an anti-tumor role affecting cell viability and apoptosis in gastric cancer. MiR-876 modulates EMT via periostin, with bioinformatics confirming its binding to periostin. Periostin in hepatic stellate cells upregulates genes like α-SMA and collagen. Elevated miR-876 boosts E-cadherin but reduces N-cadherin and vimentin, while reduced miR-876 leads to EMT downregulation and collagen expression enhancement, ultimately inhibiting periostin and EMT [130].

Long non-coding RNAs (LncRNAs) also play a role in pathological pathways, with some being aberrantly expressed in certain tumors. Pancreatic cancer cells (PCCs) secrete LINC01133-rich exosomes to PSCs, which increases LINC01133, a type of lncRNA, is observed in lung squamous cell carcinoma (LSCC) controlling tumorigenesis. periostin secretion from PSCs and contributes to the induction of EMT. Periostin promotes the secretion of LINC01133-rich exosomes from PCCs and increases its expression. LINC01133 interacts with the enhancer of Zeste Homolog 2 (EZH2) and causes H3K27 trimethylation, inhibiting the oncogene protein Axis inhibition protein 2 (AXIN2) and suppressing GSK3 [131]. This pathway prevents the degradation of β-catenin and controls EMT through epigenetic regulation of AXIN2. Periostin regulates LINC01133 expression through the EGFR pathway, which plays an important role in tumor development [131, 132]. Periostin reduction induces interactions between EGFR and Ras and Rab interactor 1 (RIN1), leading to the loss of EGFR stability. Periostin also controls the expression level of RIN1 and stops the degradation of EGFR, inhibiting periostin depletion. ChIP-qPCR assays show that periostin increases the expression of c-myc binding to the LINC01133 promoter, responsible for many cancers. Periostin also stimulates exosome secretion by PCCs, enhancing the expression of LINC01133 [131, 132]. Investigating various pathways that exert periostin effects in increasing chemoresistance is crucial. Accurate examination of periostin signaling pathways helps inhibit periostin effects by neutralizing the components of the pathway. So, according to these findings, periostin is responsible for the mesenchymal cell population growth in tumor cells following chemotherapy.

Conclusions and future outlook

Periostin promotes the growth of cancer cells in various tumor types, including prostate cancer, in addition to the initial malignancies of the esophagus, stomach, and large intestine. Cell death is triggered and the cytotoxic effect of anti-tumor medications is increased when periostin signaling is neutralized. As a result, this protein has been found to be a predictor of a worse prognosis and a possible target for anticancer therapy. The aforementioned molecular messengers may be impacted by novel medications that target the periostin signaling system. Changes that don’t interfere with healthy cells’ ability to operate normally after treatment should be included in the selection of molecular targets. However, it is a major barrier to precisely focusing the therapeutic effects of the targeted drug to exclusively inhibit the growth of cancer in the pharmacological regulation of periostin expression. This is because periostin is usually found in cells that are not malignant and is involved in a number of interactions with different molecules. To further dissect the double-edged role of periostin in cancer progression, future research should focus on elucidating the specific pathways through which periostin exerts its effects. Investigating the molecular mechanisms that differentiate its tumor-promoting activities from its inhibitory functions will be crucial. This could involve examining how periostin derived from various cellular sources—such as tumor cells versus stromal cells—interacts with distinct integrin receptors, leading to divergent signaling outcomes. Moreover, the potential for targeting both tumor-derived and stroma-derived periostin simultaneously presents an innovative therapeutic strategy. Such an approach could enhance treatment efficacy by disrupting the supportive roles periostin plays in both cancer cell proliferation and the tumor microenvironment. Developing dual-targeting therapies may involve the use of monoclonal antibodies or small-molecule inhibitors designed to neutralize periostin’s activity across different contexts. Additionally, exploring the timing and dosage of periostin-targeting interventions could optimize therapeutic outcomes, as the protein’s effects are concentration-dependent. Understanding the dynamics of periostin expression during cancer progression and treatment responses will be essential for designing effective targeted therapies.

Abbreviations

ECM

Extracellular matrix

POSTN

Periostin

EMT

Epithelial-mesenchymal transition

cDNA

Complementary DNA

ORF

Open reading frame

NSCLC

Non-small cell lung cancer

PLF

Periostin-like-factor

FAK

Focal adhesion kinase

CTD

Carboxyl-terminal domain

CCN3

Cellular Communication Network Factor 3

BMP-1

Bone morphogenetic protei-1

PBLs

Peripheral blood lymphocytes

CRC

Colorectal cancer

ER

Endoplasmic reticulum

NPC

Nasopharyngeal carcinoma

IBC

Invasive breast carcinoma

CAF

Cancer-associated fibroblast

LOX

Lysyl oxidase

VEGF-C

Vascular endothelial growth factor-C

EGFR

Epidermal growth factor receptor

MMP-9

Matrix metalloproteinase-9

NF-κB

Nuclear factor κB

CSCs

Cancer stem cells

TAM

Tumor-associated macrophages

IDC

Invasive ductal breast carcinoma

EGFR

Epidermal growth factor receptor

Author contributions

M.N-A, H.Z, and Kh.Kh conceived the hypothesis and designed the study. All of the authors wrote the manuscript text. F.F created the figures. Kh. Kh edited and supervised the study. All authors read and approved the final manuscript.

Funding

There is no foundation for this study.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have read the manuscript and given their consent for publication.

Competing interests

The authors declare no competing interests.