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9 March 2021

Cancer-Associated Fibroblast-Induced Resistance to Chemotherapy and Radiotherapy in Gastrointestinal Cancers

,
and
1
Department of Surgery, Ajou University School of Medicine, Suwon 16499, Korea
2
Infamm-aging Translational Research Center, Ajou University School of Medicine, Suwon 16499, Korea
3
Department of Biomedical Science, Graduate School of Ajou University, Suwon 16499, Korea
*
Author to whom correspondence should be addressed.
Cancers2021, 13(5), 1172;https://doi.org/10.3390/cancers13051172
This article belongs to the Special Issue Cancer-Associated Fibroblast
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Simple Summary

Gastrointestinal (GI) cancers are primary malignant tumors associated with cancer-related deaths worldwide. Although chemotherapy and radiotherapy are essential modalities to improve patient survival, many patients show resistance to these therapies. Various clinical studies have suggested that cancer-associated fibroblasts (CAFs) play a significant role in this resistance. In this review, we discuss CAF-produced cytokines, chemokines, growth factors, and exosomes, as well as desmoplastic reactions, all of which could be involved in cancer therapy resistance. In the future, the heterogeneity of CAFs should be considered such that CAF subtypes involved in cancer therapy resistance may be identified, thus improving the efficacy of chemotherapy and radiotherapy in GI cancers.

Abstract

In the past few decades, the role of cancer-associated fibroblasts (CAFs) in resistance to therapies for gastrointestinal (GI) cancers has emerged. Clinical studies focusing on GI cancers have revealed that the high expression of CAF-related molecules within tumors is significantly correlated with unfavorable therapeutic outcomes; however, the exact mechanisms whereby CAFs enhance resistance to chemotherapy and radiotherapy in GI cancers remain unclear. The cells of origin of CAFs in GI cancers include normal resident fibroblasts, mesenchymal stem cells, endothelial cells, pericytes, and even epithelial cells. CAFs accumulated within GI cancers produce cytokines, chemokines, and growth factors involved in resistance to therapies. CAF-derived exosomes can be engaged in stroma-related resistance to treatments, and several non-coding RNAs, such as miR-92a, miR-106b, CCAL, and H19, are present in CAF-derived exosomes and transferred to GI cancer cells. The CAF-induced desmoplastic reaction interferes with drug delivery to GI cancer cells, evoking resistance to chemotherapy. However, due to the heterogeneity of CAFs in GI cancers, identifying the exact mechanism underlying CAF-induced resistance may be difficult. Recent advancements in single-cell “omics” technologies could offer clues for revealing the specific subtypes and biomarkers related to resistance.

1. Introduction

Cancers originating from the gastrointestinal (GI) tract, including the esophagus, stomach, colorectum, liver, and pancreas, are common malignancies and are the primary cause of cancer-related mortalities worldwide [1]. The core treatment strategy for GI cancers is surgical resection. However, patients with non-resectable or recurrent disease are predominantly treated with chemotherapeutic agents or radiation techniques as a palliative measure [2]. Targeting agents and immunotherapy are recently developed alternatives for improving the survival of GI cancer patients [3]. However, most patients with advanced-stage GI cancers are resistant to these treatment modalities; thus, their survival rates remain dismal.
Several studies have investigated the mechanisms underlying resistance to therapy in cancers originating from the GI tract. These studies have focused on the tumor cells themselves, such as drug efflux through transmembrane transport proteins and anti-apoptotic protein activation [4,5]. However, to date, agents that block these pathways have not yet been applied in clinical settings. Moreover, numerous studies have revealed that the tumor microenvironment (TME) may play a pivotal role in resistance to chemotherapy and radiotherapy [6,7]. The TME of solid cancers comprises various non-cancerous cells, the extracellular matrix, and soluble factors [8,9] that enhance tumorigenesis, invasion, metastasis, and therapy resistance in cancer cells. Therefore, targeting agents that block the interaction between cancer cells and the TME may improve treatment outcomes in GI cancer patients [10].
Cancer-associated fibroblasts (CAFs) constitute a significant component of the TME in GI cancers. They are involved in cancer invasion and tumor growth through their interaction with cancer cells and immune microenvironments [11,12]. Numerous studies have reported that CAFs can trigger the resistance of cancer cells to treatments [13,14,15,16]. Therefore, CAFs have emerged as a novel treatment target to improve the efficacy of chemotherapy and radiotherapy in GI cancers. However, drugs targeting CAFs have not yet been administered to patients.
Herein, we introduce clinical evidence for CAF-induced resistance to treatments and describe the activity of CAFs in GI cancers. Furthermore, we summarize current research regarding the possible mechanism through which CAFs may evoke resistance to chemoradiotherapy in GI cancers.

2. Clinical Evidence for the Role of CAFs in Chemotherapy and Radiotherapy Resistance in GI Cancer

The desmoplastic reaction developed by the recruited fibroblasts is prominently observed in progressed GI cancers [17], and this reaction has been considered a major cause of resistance to chemoradiotherapy [18]. Some clinical studies have demonstrated that high desmoplasia is significantly correlated with poor clinical outcomes in patients with GI cancers, such as pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) [19,20,21]. Therefore, treatment strategies targeting tumor desmoplasia have mainly tried to improve the survival of patients with advanced GI cancers [11]. For example, the monoclonal antibody for fibroblast activation protein (anti-FAP mAb) showed some therapeutic effects in CRC without severe toxicity in the early phase of a clinical trial [22]. Additionally, recent phase II clinical trials testing angiotensin I receptor blockers as inhibitors of CAF activation and pegvorhyaluronidase alfa as a decomposer of hyaluronan accumulated by CAFs; these trials have described improved outcomes in PDAC patients [23,24]. Although these agents have not yet been approved as a treatment of choice for GI cancers, accumulating evidence suggests that targeting CAFs in GI cancers is promising (Table 1).
Table 1. Clinical studies investigating the role of CAFs in resistance to chemotherapy and radiation therapy in gastrointestinal cancers.
It has been confirmed through immunohistochemistry (IHC) that CAF accumulation in GI cancers is related to chemotherapy resistance. Ma et al. performed IHC for alpha-smooth muscle actin (α-SMA) in paraffin-embedded formalin-fixed (PEFF) tissues of gastric cancer (GC) patients treated with chemotherapy. The results showed that the GC tissues of patients showing resistance to chemotherapy contained more α-SMA-positive CAFs than the chemosensitive patients [25]. Other CRC studies also reported a significant correlation between a high proportion of α-SMA-expressing CAFs and resistance to 5-fluorouracil plus oxaliplatin-based chemotherapy [26].
The expression of CAF-derived molecules in human GI cancer tissues could be investigated to provide clinical evidence. Some researchers have reported a direct correlation between biomarkers originating in stromal cells and response to neoadjuvant treatment. The expression of the two markers FAP-α and C-X-C motif chemokine ligand (CXCL) 12, known as stromal cell-derived factor 1 (SDF-1), was positively associated with poor clinical outcomes in rectal cancer patients who underwent neoadjuvant chemoradiation [27,28]. Although chemoradiotherapy is the most popular modality for esophageal cancers (ESOCs), patients have frequently exhibited resistance to therapies, resulting in poor outcomes [32]. One study described the expression of CXCL1 in ESOC tissue specimens biopsied after chemoradiation. We concluded that the upregulation of CXCL1 in CAFs was an independent prognostic factor in these patients [29]. In addition, positive transforming growth factor-beta (TGF-β) expression in CAFs of ESOC tissues was significantly correlated with poor survival outcomes in patients treated with chemoradiotherapy [30]. Another group reported that high PAI-1 expression in CAFs led to considerably worse progression-free survival in ESOC patients treated with cisplatin [31].
Large-scale cancer genome studies using high-throughput technologies have provided comprehensive molecular profiling information for solid cancers [33]. The Cancer Genome Atlas (TCGA) consortium has suggested molecular subgroups and treatment targets based on a genome-scale analysis using bulk tumors of large cohorts [34,35,36,37,38]. However, considering the role of non-cancerous cells in the bulk tumors on cancer progression and therapeutic efficacy, the meanings of these cell fractions should be investigated. Algorithms including ESTIMATE [39], CIBERSORT [40], EPIC [41], and MCP-counter [42] can predict the proportion of stromal or immune cells in bulk cancer tissues. Consequently, the implications of the accumulation of these cells in GI cancer patient prognosis can be inferred. Recent high-throughput transcriptome analyses of GI cancers have highlighted that stroma-related genes have unfavorable outcomes in patients with various types of GI cancers, including GC, CRC, PDAC, and hepatocellular carcinoma [43,44,45,46,47]. However, these results were obtained using surgical specimens from patients who underwent curative resection, with or without subsequent adjuvant systemic treatment. To define the correlation between gene expression and response to chemotherapy, expression analyses in pretreated samples from patients subjected to preoperative chemotherapy can undoubtedly reflect their responsiveness to chemotherapy based on gene expression. Our recent data obtained using NanoString transcriptome analysis revealed that stroma-related gene expression in pretreated endoscopic biopsy tissues of GC patients who underwent preoperative chemotherapy significantly correlated with an inadequate response to chemotherapy [15]. Although NanoString transcriptome analysis screens a limited number of genes, it could be applied to a small number of samples, such as endoscopic biopsy specimens. The results implied that the high expression of stroma-related genes in the biopsied tissues of GC patients might require a novel treatment strategy. This strategy may improve the efficacy of chemotherapy for patients with GC (Figure 1). However, our study had some limitations, including a low number of enrolled patients. Another study with a large number of GC patients who had undergone neoadjuvant treatment showed that several genetic mutations could serve as predictive markers for chemotherapy response [48]. However, future studies investigating TMEs should be conducted to assess their role in therapy resistance.
Figure 1. Gene expression patterns in pretreated gastroscopically biopsied tissues of patients who underwent preoperative chemotherapy (modified from Ham et al., 2019, Mol Cancer [15]. (A). Flow diagram presenting the study scheme for the comparison of gene expression patterns using the nCounter system between chemotherapy responders and non-responders. (B). Heatmap depicting different gene expression patterns between chemotherapy responders and non-responders. Blue-colored cells in the table to the right of the heatmap indicate stroma-related genes. (C). Nine stroma-related genes were found in non-responders.
Collectively, these findings indicate that CAF accumulation or CAF-specific markers in malignant tumors originating from the GI tract are significantly related to chemotherapy or radiotherapy resistance. Therefore, the mechanisms underlying the interaction between CAFs and cancer cells would act as excellent targets to improve the responsiveness of GI cancer patients to chemoradiotherapy.

3. Origin of CAFs in GI Cancer

CAFs are fibrotic cells involved in tumor malignancy; however, the origin of these cells in GI cancer remains unclear. Numerous studies have reported that CAFs may be derived from resident fibroblasts, smooth muscle cells, endothelial cells, pericytes, bone marrow-derived stem cells, and even epithelial cells [49,50] (Figure 2).
Figure 2. Origins of cancer-associated fibroblasts (CAFs). Sources of CAFs in gastrointestinal cancers include resident fibroblasts, endothelial cells, epithelial cells, pericytes, and bone marrow-derived mesenchymal stem cells. CAFs: cancer-associated fibroblasts, MSC: mesenchymal stem cell.
Genetic and functional comparisons between fibroblasts isolated from surgically resected cancers and paired healthy tissues are relatively easier to perform than those isolated from other cell types; therefore, resident fibroblasts have been extensively explored in this context [51]. The unique characteristics of CAFs compared to normal resident fibroblasts could indicate the potential mechanism underlying the transdifferentiation of normal fibroblasts to CAFs in GI cancers. TGF-β is produced by colon cancer cells and activates the differentiation of residual colon fibroblasts into CAFs during colon cancer progression. These activated CAFs upregulate the expression of activated markers, such as α-SMA and FAPs, and produce large amounts of glycoproteins, including tenascin-C and collagen maturation enzymes, for extracellular matrix (ECM) remodeling [52]. GC cells of the scirrhous subtype also produce TGF-β, which indicates the expression of α-SMA in normal residual fibroblasts [53]. Moreover, the aforementioned study proposed that TGF-β could be reciprocally involved in the CAF-induced stemness of scirrhous GC cells and demonstrated that anti-TGF-β antibody had an inhibitory effect on tumor growth.
In PDAC, one of the distinct origins of CAFs may be pancreatic stellate cells (PSCs), the resident mesenchymal cells of the noncancerous pancreas [54]. Similar to GC, PDAC cell-induced TGF-β can activate PSCs and increase the production of ECM components such as fibronectin, collagen, and tenascin-C [55]. Additionally, the sonic hedgehog (SHH) protein expressed in PDAC cells contributes to tumor progression via the differentiation and motility of PSCs or resident fibroblasts that already exist in the pancreatic tissue [56]. However, despite the positive effects of an antibody against SHH in the PDAC preclinical animal model [56], a clinical trial showed that the SHH inhibitor did not synergize PDAC patients with gemcitabine treatment [57].
Bone marrow-derived mesenchymal stem cells (MSCs) may act as a potential source of CAFs in inflammation-induced GC [58]. The Helicobacter-induced GC mouse model reveals that CAFs are derived from α-SMA-positive myofibroblasts in the bone marrow, and these CAFs can form a tumor niche in the gastric wall and undergo tumor progression. The MSCs recruited from the bone marrow may act as a source of CAFs in PDAC and pancreatic endocrine tumors [54,59]. MSCs exposed to PDAC cells are activated into CAF-secreting tumor-promoting proteins such as hepatocyte growth factor (HGF), epidermal growth factor (EGF), and interleukin-6 (IL-6). These proteins stimulate microvascularization, changes in the composition of the stromal framework, and tumor growth through the paracrine system [54].
Other noncancerous cells, such as endothelial cells, pericytes, and even epithelial cells, which accumulate in GI cancer, can be transformed into CAFs through cell transition mechanisms. A study using a pancreatic islet tumor mouse model revealed that fibroblast-specific protein 1 (FSP1) and CD31 double-positive cells exist in the TME. Previous studies have reported that TGF-β mediates the transition from endothelial cells to mesenchymal cells in cardiac tissues [60]. Since abundant TGF-β expression was also apparent in this tumor, the authors suggested that TGF-β-exposed pancreatic endothelial cells could be a source of CAFs [61].
Vascular pericytes are multifunctional mural cells that surround endothelial cells [62], and they are crucial in the neoangiogenesis and survival of endothelial cells during tumorigenesis [63]. Emerging evidence has indicated that neural/glial antigen 2 (NG2)-expressing pericytes are transformed into CAFs through platelet-derived growth factor-BB (PDGF-BB) stimulation in a CRC xenograft model [64]. Moreover, the expression of PDGFB and FSP1 in various types of solid tumors, including CRC, is significantly correlated with poor patient prognosis [64].
Furthermore, epithelial cells of GI organs could be a source of CAFs during carcinogenesis. In genetic PDAC mouse models, pancreatic epithelial cells are transformed into mesenchymal cells through epithelial–mesenchymal transition; these cells have a fibroblast-like phenotype, express FSP1, and are deeply involved in tumor formation. However, although these FSP1-expressing cells are similar to CAFs, it is still unclear whether these cells could be a significant source of CAFs in PDAC tumors [65]. Therefore, further studies are required to verify whether epithelial cells are a crucial source of CAFs in GI cancers.

5. Heterogeneity of CAFs in GI Cancers

Tumor heterogeneity has recently been considered a crucial factor underlying resistance to antitumor therapies, including both non-cancerous stromal cells and cancer cells. In addition, various subtypes of CAFs exist [113,114,115]. Therefore, clarifying the mechanism underlying CAF heterogeneity may provide crucial information on GI cancer progression and would enable the development of novel therapeutic approaches.
Of all the GI cancers, CAF heterogeneity is best understood in PDAC. Ohlund et al. [116] reported the existence of distinct subtypes of CAFs based on their localization within the primary tumor. The α-SMAhigh CAF subtype is in direct contact with cancer cells, whereas α-SMAlow CAFs are located distally from cancer cells, releasing proinflammatory cytokines [116]. Other studies have also explored the function of α-SMAhigh CAF subtypes. Genetically engineered PDAC mouse models with α-SMA-negative fibroblasts result in more aggressive tumors and gemcitabine resistance [117,118]. Presumably, α-SMA-expressing CAFs may suppress tumor immunity and increase tumor vascularization.
These findings suggest that the CAF subtype can be characterized and identifying the specific subtypes of CAFs that play a crucial role in GI cancer progression could present novel targets for therapy. The recent development of single-cell transcriptome technology for solid tumors has shed light on the composition of various cancerous and non-cancerous tissues, as well as the heterogeneous population of accumulated cells, through gene expression patterns [119,120]. Elyada et al. [121] conducted a single-cell analysis of PDAC CAFs and found the following three subtypes: myofibroblastic, inflammatory, and antigen-presenting. Although they did not demonstrate the function of these subtypes in chemoradiotherapy resistance, this advanced technology can provide detailed information regarding CAF heterogeneity in GI cancers.

6. Conclusions and Future Perspectives

The role of CAFs in GI cancer progression has been explored extensively over the past decade [122,123]. However, in the current review, we have focused on a substantial amount of evidence related to the correlation between CAFs and chemotherapy and radiotherapy resistance in GI cancers (Figure 3, Table 2). CAFs accumulated in GI cancers secrete IL-6 or CXLC12, which can activate signal transduction with respect to drug resistance. Inhibitors of IL-6 and CXCL12, such as tocilizumab and plerixafor, respectively, exert chemosensitizing effects on GI cancers. Growth factors, such as TGF-β1, are crucial in CAF-induced resistance to therapies; however, therapeutic strategies to target CAFs for GI cancer treatment have not yet been applied in clinical settings. More complicated mechanisms may be involved in the communication between CAFs and GI cancer cells. Recent studies have demonstrated that small extracellular vesicles, such as exosomes containing miRNAs and lncRNAs, can control the epigenetic regulation of genes related to drug response. Nevertheless, exosome-based controls for improving therapeutic responses remain underdeveloped. Another factor that complicates this avenue of research is the heterogeneity of CAFs in GI cancer. Heterogeneous CAF populations must be precisely defined to determine the specific subtypes related to therapy resistance, but this remains a challenge. Recent advances in technologies, such as single-cell “omics,” will aid the exploration of CAF subpopulations and novel biomarkers related to chemotherapy and radiotherapy resistance in GI cancers.
Figure 3. Cancer-associated fibroblasts (CAFs) orchestrate the resistance to chemoradiotherapies in the tumor microenvironment. CAFs secrete abundant chemokines, cytokines, growth factors, exosomes, and other factors.
Table 2. Cancer-associated fibroblast (CAF)-derived factors that can induce treatment resistance in gastrointestinal cancers.

Funding

This research was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, grant number 2020R1A6A1A03043539, 2020R1A6A3A13071252, and 2020R1I1A1A01070961 and a National Research Foundation of Korea (NRF) grant funded by the Korean government, and the Ministry of Science and ICT, grant number 2020R1A2C100627.

Institutional Review Board Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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