Molecular mechanism of pancreatic ductal adenocarcinoma: The heterogeneity of cancer-associated fibroblasts and key signaling pathways

Abstract

Pancreatic ductal adenocarcinoma stands out as an exceptionally fatal cancer owing to the complexities associated with its treatment and diagnosis, leading to a notably low five-year survival rate. This study offers a detailed exploration of epidemiological trends in pancreatic cancer and key molecular drivers, such as mutations in CDKN2A, KRAS, SMAD4, and TP53, along with the influence of cancer-associated fibroblasts (CAFs) on disease progression. In particular, we focused on the pivotal roles of signaling pathways such as the transforming growth factor-β and Wnt/β-catenin pathways in the development of pancreatic cancer and investigated their application in emerging therapeutic strategies. This study provides new scientific perspectives on pancreatic cancer treatment, especially in the development of precision medicine and targeted therapeutic strategies, and demonstrates the importance of signaling pathway research in the development of effective therapeutic regimens. Future studies should explore the subtypes of CAFs and their specific roles in the tumor microenvironment to devise more effective therapeutic methods.

Key Words: Pancreatic cancer; Fibroblasts; Signaling pathways; Tumor microenvironment

Core Tip: This research explored the mechanisms of action of fibroblasts in pancreatic tumors and revealed their effects on the tumor microenvironment. This study revealed that fibroblasts enhance tumor growth and metastasis through specific signaling pathways, suggesting that targeting fibroblasts may emerge as a new strategy for treating pancreatic cancer.

INTRODUCTION

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), ranks among the deadliest malignancies globally, with increasing incidence and mortality rates. Epidemiological data from the World Health Organization indicate that pancreatic cancer is the second most common cancer worldwide, yet its mortality rate ranks seventh[1]. The threat of pancreatic cancer lies in its insidious malignant nature and the difficulties associated with its treatment[2]. The global average annual incidence rate is approximately eight cases per 100000 individuals; however, the death rate often exceeds the incidence rate. The prevalence of pancreatic cancer varies by region, with developed countries typically exhibiting higher rates of illness and death than developing nations. Pancreatic cancer is the fourth most common cause of cancer fatalities in the United States and ranks lower among the causes of cancer mortality in low- and middle-income nations. The numerous risk factors for pancreatic cancer include environmental factors, genetics, and lifestyle factors[1,3]. The main risk factors[4] include age and sex differences, family history of cancer, genetic variations[5], chronic pancreatitis, obesity, and diabetes. Despite extensive research on these risk factors, the precise pathogenesis of pancreatic cancer remains elusive. Experts such as Kamisawa et al[6] have suggested that mutations in four key genes (CDKN2A, KRAS, SMAD4, and TP53) are essential in the progression of pancreatic cancer, and mutations in KRAS and variations in CDKN2A are often significant characteristics that are visible during the initial stages of pancreatic cancer. These gene alterations act as driving forces in the initiation of pancreatic cancer, as they disrupt the normal growth and division patterns of cells, leading to unchecked proliferation and tumor formation. Additionally, Takács et al[7] identified insulin receptor substrate 1 as a novel member of the EGFR signaling pathway in pancreatic cells, further expanding our comprehension of the signaling pathways involved in PDAC.

Studies of the complex molecular mechanisms underlying pancreatic cancer are paving the way for new preventive and therapeutic approaches. Given that many patients with pancreatic cancer are already in advanced stages at the time of diagnosis owing to nonspecific early signs, research on early diagnosis and improved screening strategies is also receiving significant attention[1,8]. Recent research has shown that an imbalance in the pancreatic microbiome may be linked to the onset and progression of pancreatic cancer, thereby offering a new perspective for disease prevention and treatment. Dambuza and Brown[9] reported that fungi of the genus Malassezia that interact with the complement system can induce pancreatic inflammation and accelerate the development of PDAC. However, this view was overturned by Fletcher et al[10], who did not observe an abundance of fungi in healthy and cancerous pancreatic tissue samples or significant compositional differences in the mycobiome.

MODERN DIAGNOSTIC AND THERAPEUTIC RESEARCH

Surgery is currently the only potentially curative option; however, fewer than 20% of patients qualify for this treatment. Even after surgical procedures, the risk of recurrence and metastasis remains high, which is pivotal in causing the majority of patient deaths[11]. Consequently, developing new treatment strategies and judicious choices among current therapies are crucial for improving patient outcomes. Compared with upfront surgery or adjuvant use of gemcitabine alone, neoadjuvant therapy based on gemcitabine combinations, including surgery followed by adjuvant gemcitabine, appears to increase overall survival in patients with resectable or borderline resectable pancreatic cancer[12]. For borderline resectable PDAC, neoadjuvant therapy, including chemotherapy and occasional radiotherapy, is preferred to increase the probability of achieving a negative resection margin. Modern polychemotherapy regimens, such as FOLFIRINOX, have shown potential, although the efficacy of radiotherapy remains to be established[13]. With respect to targeted therapy for PDAC, Qi et al[14] reported that fibroblasts linked to cancer secrete exosome-derived miRNAs that target ACSL4, leading to gemcitabine resistance in PDAC cells. Chemotherapy, which includes gemcitabine, FOLFIRINOX, and albumin-bound paclitaxel, is the standard treatment for advanced PDAC; however, it does not improve the survival rate of patients[15,16].

Liquid biopsy holds great promise, particularly in molecular screening and therapeutic directions for individuals with advanced pancreatic cancer. This technique aids in identifying mutable genes, and some patients have already pursued matched targeted treatments in early clinical trials[17].

Therapeutic strategies against PDAC have progressed in the realms of targeted therapies and immune checkpoint inhibitors[18,19]. However, their effectiveness is limited when tackling the unique and immunologically ‘cold’ tumor microenvironment (TME) of PDAC[18].

The importance of individualized treatment approaches has been increasingly recognized, particularly for difficult-to-treat PDAC, owing to the current lack of effective chemotherapeutic options. The absence of early detection of precursor lesions and poor prognosis due to micrometastases highlight the need for personalized therapeutic interventions and targeted treatment modalities[20].

Despite intense research on PDAC treatments, most strategies targeting the fibrotic stroma and immunosuppressive pathways have not been successful owing to the complexity of the TME. These findings underscore the pressing need for multimodal treatment approaches and complex therapeutic strategies for PDAC[21].

In conclusion, the high mortality rate, intricate risk factors, and clinical management challenges associated with pancreatic cancer are global public health issues. Future research directions include elucidating the mechanisms of pancreatic cancer pathogenesis and developing more effective prevention and treatment strategies aimed at alleviating the societal and medical burdens imposed by this deadly disease.

Cancer-associated fibroblasts

Functions: Cancer-associated fibroblasts (CAFs) play crucial roles in the PDAC TME and promote tumor proliferation, growth, invasion, metastasis, angiogenesis, and chemoresistance through various cytokines.

Heterogeneity studies have identified two distinct CAF subgroups in PDAC: Those that express fibroblast activation protein (FAP) and those that express α-SMA. These subgroups manifest opposing roles in the TME. FAP+ CAFs may facilitate tumor growth, whereas α-SMA+ CAFs may inhibit pancreatic cancer progression. Wang et al[22] discovered a new metabolic subpopulation of CAF with abnormal glucose metabolism. Further analysis revealed that the glycolytic capacity of the subpopulation was abnormally increased, affecting glucose metabolism in cancer cells and T cells through interactions and ultimately affecting the efficacy of immunotherapy for pancreatic cancer (Table 1).

Table 1 Characteristics and functions of cancer-associated fibroblasts subtypes.

Types	Origin	Markers	Role in TME
MyCAFs	Pancreatic cells, PSCs	α-SMA, FAP, SMA, PDGFβ	Facilitate tumor cell invasion, migration, drug resistance[23-27]
ICAFs	Bone marrow-originated monocytes	IL-6, IL-1β	Promote tumor inflammation, immune evasion, tumor progression[25,26,33,34]
ApCAFs	Mesenchymal cells	MHC-II, RORγt	Enhance tumor aggression, amplify immune checkpoint inhibitor efficacy[25,35,36]

MyCAF: Myofibroblast-like cancer-associated fibroblast; ICAF: Inflammatory cancer-associated fibroblast; ApCAF: Antigen-presenting cancer-associated fibroblast; PSC: Pancreatic stellate cell; TME: Tumor microenvironment.

Therapeutic strategies: Targeting these distinct CAF subgroups can improve PDAC treatment outcomes. For example, targeting FAP+ CAFs may be an effective strategy, whereas the presence of α-SMA+ CAFs may help to control PDAC progression. Moreover, the role of CAFs should be considered in immunotherapy and other treatment approaches.

Myofibroblast-like CAFs

Myofibroblast-like CAFs (myCAFs) are a distinct subtype of CAFs that act as major cellular components in the PDAC microenvironment and promote or suppress tumor growth[23,24]. Primarily identified by Elyada et al[25] through single-cell RNA sequencing and immunohistochemistry, myCAFs originate from pancreatic cells and surrounding pancreatic stellate cells (PSCs). These cells are distinguished by their high levels of α-SMA expression[26] and exhibit muscle-like contractile functions. In addition to α-SMA, myCAFs express FAP, SMA, and PDGFβ, indicating their multifunctional and crucial roles in extracellular matrix (ECM) structure, signal transduction, and intercellular communication.

MyCAFs remodel the TME by secreting ECM proteins, including matrix metalloproteinases (MMPs), fibronectin, and collagen. This secretion affects the physical properties of tumors and enhances tumor cell invasion. Their unique contractility further adjusts the stiffness of the TME, consequently influencing tumor cell mobility and dispersal[27].

Within the TME, the contractility of myCAFs and their ECM regulatory activities collectively affect tumor cell invasion, proliferation, and migration[25]. The reciprocal interaction between tumor cells and myCAFs stimulates the formation of myCAFs through factors such as transforming growth factor-β (TGF-β) and PDGF, which adjust the ECM composition and physical properties.

Mucciolo et al[28] demonstrated that the ERBB2 signaling pathway in myCAFs is activated by TGF-β and is mediated through an autocrine process involving amphiregulin. ERBB activation intensified the enhancement of local PDAC metastasis by myCAFs, demonstrating the functional significance of myCAF heterogeneity. Sun et al[29] reported that the inflammatory factor chemokine ligand 3 promotes the dissemination of cancer cells from their original location to various regions of the body. This ligand aids cancer cells in evading the immune system by activating myofibroblasts. By selectively eliminating LRRC15-rich myCAFs, the total number of tumor fibroblasts is significantly reduced, and the CAF composition is restored toward that of common fibroblasts[30].

MyCAFs significantly influence the tumor response to treatment. By altering the composition and density of the ECM, they increase the physical resistance of tumors, thereby reducing the penetrability and efficacy of anticancer drugs. Additionally, the cytokines and chemokines secreted by myCAFs, including growth factors and immunosuppressive molecules, promote the survival and proliferation of tumor cells. This secretion inhibits the immune system’s capacity to identify and eliminate tumor cells.

In summary, myCAFs play a pivotal role in PDAC progression. They drive tumor cell proliferation and invasion, significantly affecting the tumor response to treatment. Moreover, myCAFs stimulate tumor growth and immune evasion through the secretion of various factors. These insights provide theoretical support for the creation of novel anticancer treatment strategies that specifically target myCAFs.

Inflammatory CAFs

Research[25] utilizing single-cell RNA sequencing and immunohistochemical analysis has shown that inflammatory CAFs (iCAFs) mainly originate from bone marrow-derived monocytes. Monocytes that are attracted to factors, such as CSF1, released by tumor cells after tumor formation are converted into iCAFs. By secreting cytokines and chemokines, such as interleukins, iCAFs promote tumor inflammation and immune evasion. They play a crucial role in immune modulation and thus hold potential as targets for immunotherapy.

Schwörer et al[31] reported that hypoxic conditions[32] or the overexpression of HIF1α can trigger the activation of NF-κB inflammatory genes, thereby promoting the development of the iCAF phenotype. iCAFs create a conducive growth environment for tumor cells by secreting inflammatory promoters such as IL-6 and IL-1β, among other cytokines. This secretion facilitates tumor cell proliferation and invasion and modulates immune cell function, thereby promoting immune evasion. Hypoxia not only affects the targeted encapsulation process of extracellular vesicles (EVs) secreted by fibroblasts but also leads to the ability of EVs derived from PSC under hypoxic conditions to increase the proliferation and gemcitabine resistance of tumor cells both in vitro and in vivo[33,34]. In the pancreatic cancer microenvironment, iCAFs not only promote inflammation but also strengthen interactions with tumor cells, greatly exacerbating tumor malignancy. By secreting growth factors and chemical signals, iCAFs increase the invasiveness and migratory ability of tumor cells. They also modify the composition and density of the ECM, affecting the physical contact between tumor cells and their surrounding environment.

In hypoxic environments, tumor cells promote the formation of iCAFs by producing signaling molecules such as IL-1α and HIF1α[35]. Under hypoxic conditions, these iCAFs exhibit a more pronounced inflammatory phenotype, further aggravating tumor progression and immune evasion[32]. The functions of iCAFs[26] in promoting tumor growth, invasion, and migration and regulating immune reactions within the microenvironment underscore their importance in the development of pancreatic cancer. Therefore, a deeper understanding of the mechanisms underlying the action of iCAFs is crucial for developing new therapeutic approaches to treat pancreatic cancer.

Antigen-presenting CAFs

Elyada et al[25] reported that antigen-presenting CAFs (apCAFs) are formed through the stimulation of the JAK/STAT signaling pathway and the transcription factor RORγt, which are influenced by IL-6 and IL-23 secreted by tumor cells. In the pancreatic cancer microenvironment, apCAFs can stimulate CD4+ T cells by expressing major histocompatibility complex class II (MHC-II) and costimulatory molecules[35], potentially enhancing the effectiveness of immune checkpoint inhibitors[25].

Huang et al[36] reported that apCAFs can transdifferentiate from mesenchymal cells and regulate the immune reaction in pancreatic cancer by inducing CD4+ T cells to differentiate into Tregs, thus offering a potential target for immunotherapy. Additionally, apCAFs play pivotal roles in influencing tumor metabolism and regulating immune responses. They intensify tumor aggressiveness through the exchange of cytokines and metabolites, paracrine signal transduction, microenvironmental acidification, and scarring.

Moreover, apCAFs exhibit characteristics of both myofibroblastic and inflammatory states within the TME, revealing the heterogeneity of fibroblasts in pancreatic cancer[37]. Maru et al[35] highlighted the function of apCAFs in controlling CD4+ T-cell activation in PDAC. Although the treatment effectiveness of immune checkpoint inhibitors in tumors such as PDAC is limited, apCAFs provide an alternative mechanism for CD4+ T-cell activation through the expression of MHC II. This unique mode of immune activation may help overcome the challenges associated with immunotherapy.

Future studies should delve deeper into the molecular mechanisms and immunomodulatory functions of apCAFs. The goal was to develop therapeutic strategies targeting these cell populations to improve patient survival rates[37].

SIGNALING PATHWAYS

PDAC is closely linked to the abnormal activation of multiple signaling pathways. KRAS mutations are the most prevalent genetic events in PDAC, leading to the initiation of several signaling pathways that increase cell growth and survival. Other signaling pathways, such as the TGF-β, Hedgehog (Hh), Wnt/β-catenin, and JAK/STAT pathways, play significant roles in PDAC development.

The TME in PDAC is particularly rich in ECM components, which provide structural support and influence cellular behavior. The constituents of the ECM, including collagen and hyaluronic acid, engage with receptors located on the exterior of tumor cells, such as integrins, to activate downstream signaling pathways that promote invasion and migration.

Additionally, the physical properties of the ECM, such as stiffness and density, can influence mechanical signal transduction, thereby affecting tumor growth and spread.

There is a dynamic interplay between signaling pathways and the ECM in PDAC. The activation of signaling pathways can influence the structure and reconfiguration of the ECM, whereas changes in the ECM can influence the activity of signaling pathways. For example, the TGF-β signaling pathway not only plays a critical role in PDAC development but also regulates the synthesis and degradation of ECM components, affecting the stiffness and composition of the TME.

Gaining insights into these interactions is essential for developing targeted therapeutic strategies for PDAC treatment. By targeting both signaling pathways and ECM components, disrupting the supportive TME and inhibiting tumor progression more effectively may be possible (Table 2).

Table 2 Key signaling pathways in pancreatic cancer: Main functions and impacts.

Signaling pathway	Main function	Impact on pancreatic cancer
TGF-β	Regulates cell proliferation, differentiation, and apoptosis	Initially inhibits tumor cell proliferation, later promotes tumor cell proliferation and metastasis, regulates ECM composition and remodeling, affects chemotherapy efficacy[38-44]
Hedgehog (Hh)	The growth of the pancreas	Promotion of Hh signaling in CAFs, inhibition of Hh signaling can induce apoptosis, suppress cell proliferation, and increase sensitivity to chemotherapeutic agents[45-49]
Wnt/β-catenin	Promotion of the expression of tumorigenic factors	Promotes cancer cell proliferation and growth, regulates ECM remodeling, affects drug resistance[57-60]
JAK/STAT	Cell survival, proliferation, and invasion	Supports tumor cell survival and invasion; enhances the secretory capacity of CAFs; affects drug resistance[26,43,61-64,66,67]

ECM: Extracellular matrix; CAF: Cancer-associated fibroblasts.

TGF-β signaling pathway

TGF-β is a pivotal signaling molecule that plays a significant role in the interaction between CAFs and pancreatic cancer cells. CAFs promote the proliferation, invasion, and migration of pancreatic cancer cells through TGF-β secretion. This molecule binds to TGF-β receptors on the surface of tumor cells, activating both the SMAD and non-SMAD pathways. These pathways affect the proliferation, differentiation, and apoptosis of cells. TGF-β acts as a suppressor during the initial phases of pancreatic cancer by halting the multiplication of tumor cells. However, as tumors progress, cancer cells often develop resistance to TGF-β signaling, thus promoting their proliferation and metastasis[38,39].

TGF-β can also modulate ECM components and their remodeling, facilitating the migration pathways of tumor cells. Hussain et al[38] reported that TGF-β plays a complex dual role in PDAC progression, acting as a tumor suppressor during nonmetastatic stages and facilitating tumor progression during metastatic stages[40].

Studies have shown that the TGF-β signaling pathway plays a decisive role in the invasiveness and metastatic capability of pancreatic cancer cells. For example, Lu et al[41] reported that TGF-β upregulates the expression of the microRNA miR-147b, leading to posttranscriptional silencing of KMT2D, thereby inhibiting KMT2D protein expression. The absence of KMT2D triggers the expression and release of activin A, which activates the atypical p38 MAPK-mediated signaling pathway. This causes cancer cells to undergo mesenchymal transition, which enhances their plasticity, invasiveness, and metastatic capability. Additionally, TGF-β facilitates epithelial mesenchymal transition, a key step in tumor metastasis[42], and promotes myofibroblast differentiation by downregulating IL-1R1 expression[43].

The TGF-β signaling pathway also plays a crucial role in modulating the efficacy of chemotherapeutic drugs for pancreatic cancer. Drubay et al[40] discovered that the inhibition or downregulation of transforming growth factor-β receptor II (TGFBR2) expression can accelerate tumor growth and promote tumor cell spread, highlighting the importance of this pathway in resistance to drugs such as gemcitabine. This study provides a basis for potential treatments that target the TGF-β signaling pathway to increase chemosensitivity.

With respect to the therapeutic potential of the TGF-β signaling pathway, research has explored the disruption of specific signaling molecules via the use of small-molecule drugs or siRNAs. For example, targeting the SBF2 gene via siRNA can significantly slow the proliferation of pancreatic cancer cells and promote their apoptosis. USP33 was found to maintain the activity of TGF-β signaling by preventing the degradation of TGFBR2, thereby contributing to tumor progression. Disrupting USP33 can inhibit this effect[44].

An in-depth study of the complex role of TGF-β signaling in pancreatic cancer development is essential for the advancement of targeted treatment approaches. Future research should focus on uncovering the intricacies of TGF-β signaling mechanisms in pancreatic cancer and using this knowledge to design innovative treatments, especially for patients unresponsive to conventional therapies. Continued research will not only elucidate the function of TGF-β in pancreatic cancer but will also help explore new therapeutic frontiers.

Hh signaling pathway

Lau et al[45] highlighted the function of the Hh pathway in the growth of the pancreas and confirmed its continued activity in adult tissues. This finding underscores the ongoing influence of the pathway on both development and disease. Walter et al[46] reported that Smoothened overexpression might result in the stimulation of Hh signaling in pancreatic CAFs. Thayer et al[47] reported that this pathway was active in pancreatic cancer cells. Inhibition of this pathway by cyclopamine induces apoptosis and inhibits cell proliferation.

Feldmann et al[48] reported that the Hh signaling inhibitor cyclopamine reduced the invasiveness of pancreatic cancer cells in vitro. Additionally, in combination with gemcitabine, cyclopamine inhibited tumor metastasis and reduced the size of primary tumors in vivo.

Onishi and Katano[49] investigated the activation of the Hh pathway under hypoxic conditions and reported that it is related to the malignant phenotype of pancreatic cancer. These findings suggest a link between hypoxia and enhanced Hh signaling. Mathew et al[50] reported that controlled dosing could modulate the effect of the Hh pathway on pancreatic cancer, providing insights into the failure of some Hh-blocking therapies. Jeng et al[51] demonstrated that Sonic Hh secretion in the TME is crucial for cancer progression. Furthermore, Kayed et al[52] examined the activity and role of the Indian Hh signaling pathway in pancreatic cancer, emphasizing its importance in malignancies. This highlights the importance of optimal dosing for therapeutic strategies. The overexpression of Gli1 or Gli2 has been observed in various chemoresistant malignancies[53]. Studies have shown[54-56] that after the Smo gene is knocked down, the Hh signaling pathway can be suppressed, resulting in reduced resistance of pancreatic cancer cells to gemcitabine, indicating that inhibition of the Hh signaling pathway may increase the sensitivity of these cells to chemotherapeutic drugs.

Overall, the Hh signaling pathway is crucial for pancreatic cancer development through various mechanisms, including the activation of CAFs, the regulation of tumor cell survival and growth, and the TME. These studies help elucidate the pathophysiology of pancreatic cancer and provide a scientific basis for developing anticancer strategies targeting the Hh pathway.

Future studies should explore the intricacies of this pathway to develop more precise and effective treatments, particularly for patients who do not respond to conventional therapies.

Wnt/β-catenin signaling pathway

The interaction between CAFs and pancreatic cancer cells is significantly influenced by the Wnt/β-catenin signaling pathway, which secretes Wnt ligands and activates Frizzled receptors on tumor cells, and the β-catenin signaling pathway. β-catenin translocates to the nucleus, prompting the expression of factors that promote tumorigenesis, such as cyclin D1 and myc proto-oncogene protein (c-Myc). These factors drive the proliferation and growth of pancreatic cancer cells.

Zhang and Wang[57] demonstrated that the long noncoding RNA H19, expressed by CAFs, activates the Wnt/β-catenin pathway in neighboring colorectal cancer cells, thereby promoting cancer cell growth. This revealed a new mechanism by which CAFs use molecular mediators to affect cancer cells. Ma et al[58] reported that pancreatic cancer cells can activate CAFs via TGF-β1. This interaction potentially regulates the Wnt/β-catenin pathway, induces thrombospondin expression through the p-Smad2/3 pathway, and influences tumor biological behavior.

Yan et al[59] addressed the issue of pancreatic cancer drug resistance and suggested that the regulation of the Wnt/β-catenin pathway can activate CAFs. This process involves ECM remodeling and provides new targets for the treatment of drug resistance. Zhou et al[60] reported that Plasmacytoma Variant Translocation 1 could activate Wnt/β-catenin signaling and autophagy, aiding pancreatic cancer cells in countering gemcitabine. These findings suggest a potential avenue to overcome chemoresistance.

In summary, the Wnt/β-catenin pathway is key to the interplay between CAFs and pancreatic cancer cells and may be a new therapeutic strategy. Future studies should further investigate the role of this pathway in the TME and its potential to optimize therapeutic effects. Continued research in this area can deepen our understanding of the Wnt/β-catenin signaling pathway and its implications for more effective therapeutic strategies against pancreatic cancer.

JAK/STAT signaling pathway

Cytokines secreted by CAFs, such as IL-6 and IL-11, activate receptors located on the tumor cell surface, promoting the JAK/STAT signaling pathway. This activation supports tumor cell survival, proliferation, and invasion[43,61,62]. Activated STAT3 enhances the secretory capacity of CAFs, thereby creating an immunosuppressive TME[26,63]. Sperb et al[64] reported that mutations in or the absence of p53 in PDAC cells lead to the continuous activation of STAT3. In response, paracrine activation of CAFs/PSCs enhances the stromal response, advancing tumor progression and gemcitabine resistance.

In PDAC, IL-1 induced JAK/STAT signaling is antagonized by TGF-β. This interaction increases CAF heterogeneity and decreases therapeutic effectiveness[65]. Hu et al[66] reported that overexpression of circFARP1 (hsa_circ_0002557) in CAFs activated the STAT3 signaling pathway in pancreatic cells by increasing the expression and release of leukemia inhibitory factors in CAFs, thereby increasing the resistance of PDAC to gemcitabine.

Recent research has shown that the simultaneous application of mitogen-activated protein kinase, STAT3, and PD-1 inhibitors enhances the recruitment and functionality of activated and memory T cells, overcoming resistance to immunotherapy in patients with PDAC[62]. This underscores the necessity to consider the diversity and mechanisms of interaction with tumor cells of therapeutic approaches targeting CAFs. CAFs play a role in treatment resistance through JAK/STAT signaling by participating in chemotherapy drug metabolism and transport, directly affecting tumor cell therapeutic responses[67]. Understanding the molecular characteristics of CAFs and their role in the TME is essential for formulating effective treatment strategies.

In summary, the JAK/STAT signaling pathway is key to the interaction between CAFs and pancreatic cancer cells. These findings may provide new therapeutic strategies, especially considering the diversity of CAFs and their role in the TME.

INTERACTION OF CAFS WITH OTHER COMPONENTS

Interactions between fibroblasts, PSCs, and immune cells

PSCs play a crucial role in the TME of pancreatic cancer by secreting abundant ECM proteins (such as collagen) to create a dense stromal environment. This not only directly promotes the invasion and migration abilities of pancreatic cancer cells but also induces the activation of CAFs through the secretion of proinflammatory factors such as TGF-β[68-70]. The synergistic effect between PSCs and CAFs further regulates the stiffness and structure of the TME, significantly enhancing the growth potential and drug resistance of tumors[70]. This process reveals the crucial role of PSCs in the onset and progression of pancreatic cancer as well as their complex mechanisms in promoting tumor progression by modulating the TME.

Immune cells exhibit intricate interactions with CAFs in the TME of pancreatic cancer[71] and effectively recruit and activate specific immune cell populations, such as Tregs and tumor-associated macrophages (TAMs), through the release of chemokines and cytokines. This interactive mechanism has profound effects on tumor progression. On the one hand, the collaboration between CAFs and Tregs can significantly suppress antitumor immune responses, thereby facilitating immune escape. In contrast, the interplay between CAFs and TAMs further supports tumor growth and metastasis through the secretion of immunosuppressive factors such as IL-10 and TGF-β[72-74]. Notably, the original antitumor activity of natural killer (NK) cells, which are influenced by CAFs, is significantly suppressed, further demonstrating the crucial role of CAFs in regulating the tumor immune microenvironment[75]. Endothelial cells support the growth and progression of pancreatic cancer by promoting the formation of new blood vessels, also known as tumor angiogenesis[76]. CAFs facilitate endothelial cell proliferation and neovascularization by secreting vascular endothelial growth factors and other factors[15]. These newly established blood vessels supply nutrients and oxygen to tumor cells, thereby accelerating tumor growth[76].

ECM remodeling

CAFs actively regulate the secretion of matrix MMPs and tissue inhibitors of metalloproteinases. This modulation is essential for the degradation and reorganization of the ECM, providing the necessary physical pathways for the invasive migration of activated tumor cells[77]. Structural reorganization of the ECM significantly affects the cell signaling network in the TME. For example, CAFs continuously promote tumor-associated signaling events by releasing key growth factors, ECM components, and diverse enzymes that were previously tethered by the ECM and altered aspects of structure and function. These changes increase density and stiffness, thereby facilitating the invasive capabilities and migration of tumor cells[78,79]. For example, the secretion of collagen and fibronectin by CAFs strengthens ECM cross-linking, leading to increased stiffness in the TME and providing a more stable scaffold for tumor cells[26].

ECM remodeling processes regulated by CAFs modulate various biochemical and physical properties of the TME. This directly affects tumor cell growth, survival, and energy metabolism. Concomitantly, CAF-mediated ECM remodeling is associated with changes in the tumor cell phenotype, drug responsiveness, and immune escape mechanisms. The ECM serves as an obstacle to drug delivery, attenuating the effectiveness of chemotherapy by altering vascular functionality and tumor tissue permeability through increased interstitial fluid pressure[61].

Synergistic interactions between tumor cells and CAFs, such as the initiation of extracellular signal-regulated kinases, phosphatidylinositol 3-kinase/Akt, and Wnt/β-catenin signaling pathways, strengthen adhesion to the ECM and affect the dynamic rearrangement of ECM components. These mechanisms accelerate tumor invasion and metastasis, trigger angiogenesis, foster inflammation, regulate tumor metabolism, and may cause resistance to anticancer drugs[80,81].

The diversity of CAFs is a key driver of the structural and functional variability of the ECM. Different CAFs participate in tumor progression through various biomolecules and cellular signaling mechanisms. For example, some CAFs release proinflammatory cytokines that activate tumor-promoting inflammatory responses, whereas others modulate immune responses through the secretion of anti-inflammatory molecules, thereby affecting tumor development and treatment outcomes[82]. Immune cells, particularly neutrophils and macrophages, also play critical roles in this process by regulating ECM properties in coordination with PSCs to promote PDAC development.

In summary, CAFs in the pancreatic cancer microenvironment play multiple roles in ECM remodeling. They not only physically change the tumor environment but also profoundly influence key biological behaviors of tumor cells through the release of different signaling molecules. The development of treatments targeting CAFs and the ECM remodeling process they mediate could present new potential avenues in the therapeutic landscape of pancreatic cancer.

CONCLUSION

This article extensively examines the therapeutic approaches and molecular mechanisms underlying PDAC, focusing on the heterogeneity of CAFs and their critical role in disease progression. An integrated review of epidemiological trends and key molecular factors revealed the determinative impact of genetic mutations in CDKN2A, KRAS, SMAD4, and TP53 on pancreatic cancer progression. Additionally, this study underscores the importance of the TGF-β and Wnt/β-catenin signaling pathways in the development of pancreatic cancer and their potential application in the formulation of new therapeutic strategies.

Future studies should delve more deeply into CAF subtypes and their roles in the TME to discover more effective treatment modalities. Furthermore, research should be dedicated to revealing the deeper pathological mechanisms of pancreatic cancer and developing more specific therapeutic approaches. With this research, it is hoped that new realms will become available for treating pancreatic cancer, offering more effective strategies to manage this lethal disease. In conclusion, this study establishes a novel scientific basis for treating pancreatic cancer, highlighting the importance of deep signaling pathway research in the formulation of effective therapeutic strategies. This approach has the potential to achieve breakthroughs in precision medicine and targeted therapy.

ACKNOWLEDGEMENTS

I would like to express my deepest gratitude to my friends and family for their moral support and encouragement, which have empowered me to complete this thesis.