Fibroblast Subsets in Colorectal cancer: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Hao Dang.

CAFs are defined as fibroblasts surrounding malignant tumor cells and are the most abundant cell type in the tumor microenvironment of colorectal cancer (CRC). CAFs consist of various functionally heterogeneous subsets which can promote or restrain cancer progression. Although most previous research has focused on the biology of epithelial cells, accumulating evidence shows that certain CAF subsets can also importantly contribute to tumor initiation and progression, thereby possibly providing avenues for improvement of clinical care for CRC patients. However, attention needs to be paid to comprehensive characterization and reporting of the subsets being investigated in CAF studies to enable more precise identification and targeting of “unfavorable” CAFs in advanced CRC.

  • colorectal cancer
  • tumor stage
  • adenoma–carcinoma sequence
  • cancer-associated fibroblast

1. Introduction

Colorectal cancer (CRC) is the most commonly diagnosed malignancy in the gastrointestinal tract, constituting almost two million new cases and one million deaths per year worldwide [1,2][1][2]. The majority of CRC cases develop via the adenoma–carcinoma sequence [3]. This process is accompanied by sequential accumulation of (epi) genetic alterations in epithelial cells that lead to the formation of benign precursor lesions called adenomas [4]. Some of these adenomas eventually progress into invasive carcinomas. Although most previous research has focused on the biology of epithelial cells, it has become clear that the tumor microenvironment (TME), also known as the tumor stroma, plays an important role in CRC initiation and progression as well [5,6][5][6]. For instance, a high stromal content at the invasive front of CRCs is strongly correlated to an increased risk of CRC-related death [7,8][7][8]. Moreover, several studies have demonstrated that the prognostic value of the recently developed Consensus Molecular Subtypes (CMS) classification system for CRC [9] [9] can be mainly attributed to genes expressed by stromal cells, rather than tumor cells [10,11,12][10][11][12]. Of all the CMS categories, the mesenchymal or stromal CRC subtype (CMS4) is associated with the worst survival outcomes [9], thereby underlining the significant involvement of the TME in tumor progression.

The tumor stroma of CRC consists of several cell types (e.g., immune cells and endothelial cells), of which the cancer-associated fibroblasts (CAFs) are most abundant. CAFs are defined as fibroblasts surrounding malignant tumor cells [13], and consist of various heterogeneous subsets which can exert both tumor-promoting and -suppressing functions [5,6,13,14][5][6][13][14]. Many studies have shown that CAFs can make an important contribution to CRC progression. However, most of these findings have not yet been translated into applications with clinically relevant efficacy, mainly due to the considerable heterogeneity in CAF subsets and phenotypes in advanced CRCs [98,99,100,101,102][15][16][17][18][19]. To tackle this issue, Li et al. performed scRNAseq on human primary CRCs and found that CAFs seem to cluster into two major CAF types termed CAF-A (marker genes: e.g., MMP-2, FAP, and decorin) and CAF-B (marker genes: e.g., α-SMA, transgelin and platelet-derived growth factor subunit A (PDGFA)) [103][20]. Although it remains unclear how these CAF clusters are functionally involved in CRC progression, findings from clinical trials suggest that they are not exclusively composed of tumor-promoting or tumor-suppressing CAFs. For instance, therapeutic targeting of FAP-expressing CAFs (i.e., the CAF-A subset) does not appear to significantly affect clinical outcomes of patients with advanced CRC [97,104,105][21][22][23]. These results suggest that a more detailed, function-based subclassification of CAFs is required.

2. CAF subsets and functions in advanced CRC

In contrast to the scarce literature on tumor-suppressing functions of CAFs, there are quite some studies which have related various tumor-promoting functions to specific markers expressed by certain CAFs found in human CRCs (Table 1). However, as most of these CAFs have not been extensively characterized, it often remains unclear how they relate to the two major CAF clusters and whether they represent phenotypically distinct subsets or overlap with other tumor-promoting or -suppressing CAFs. In this entry, we provided an overview on (the markers of) these possible CAF subsets, stratified per tumor-promoting function which they have been linked to.

Table 1.

Examples of tumor-related functions which have been linked to factors expressed or secreted by certain cancer-associated fibroblast (CAF) populations in human advanced colorectal cancers (CRCs).

CAF Metadata Role in CRC Progression Clinical Relevance
Name of Factor Characteristics of CAFs Expressing or Secreting This Factor Characteristics of Tumors Which the CAFs Originated From CRC Proliferation CRC Invasion/Migration Angiogenesis Therapy Resistance Immune Evasion Organ Metastasis Association High Expression Levels in CAFs & Poor Clinical Outcomes
Exosomal circular RNA SLC7A6 [112]Exosomal circular RNA SLC7A6 [24] - Primary tumor;

no neo-adjuvant treatment		 ↑ ↑ - - - - Yes [112]Yes [24]
HIC-5 [109]HIC-5 [25] Co-localization with α-SMA Primary tumor ↑ - - - - - -
COX-2 [142,143]COX-2 [26][27] - Primary tumor ↑ - - - - - -
Snail-1 [110]Snail-1 [28] Co-localization with α-SMA and FAP Primary tumor ↑ ↑ - - - - Yes [144]Yes [29]
FGF-1 [111]FGF-1 [30] Vimentin-positive Primary tumor ↑ ↑ ↑ - - - -
FGF-3 [111]FGF-3 [30] Vimentin-positive Primary tumor ↑ ↑ ↑ - - - -
Wnt2 [114,115,116]Wnt2 [31][32][33] - Primary tumor;

rectum; stage II-IV; well/moderate differentiation [114].

Not described in [115,116]		Primary tumor;

rectum; stage II-IV; well/moderate differentiation [31].

Not described in [32][33]		 ↑ ↑ ↑ - - - Yes [114,115]Yes [31][32]
miRNA-21 [118,119]miRNA-21 [34][35] - Primary tumor; rectum & sigmoid; stage II-III; well/moderate differentiation; microsatellite stable; no neo-adjuvant treatment ↑ ↑ - - - ↑ Yes [117]Yes [36]
CD10 [81]CD10 [37] - Primary tumor; rectum and colon; stage II-III; well/moderate differentiation ↑ ↑ - - - - -
CLEC3B [145]CLEC3B [38] - Primary tumor - ↑ - - - - Yes [145] Yes  [38] 1
Podoplanin [79]Podoplanin [39] - - - ↓ - - - - No [79,80] No [39][40]2
SPARC [146]SPARC [41] - Primary tumor - ↑ - - - - Yes [146]Yes [41]
IGF-2 [147]IGF-2 [42] - Primary tumor = ↑ - - - ↑ Yes [147]Yes [42]
RAB31 [148]RAB31 [43] Co-localization with α-SMA and vimentin Primary tumor = ↑ - - - - Yes [148]Yes [43]
CCBE1 [149]CCBE1 [44] Co-localization with α-SMA Primary tumor - - ↑ - - - Yes [149]Yes [44]
miRNA-31 [122]miRNA-31 [45] - Primary tumor;

no neo-adjuvant treatment		 - - - ↑ - - -
miRNA-93–5p [123]miRNA-93–5p [46] - Primary tumor - - - ↑ - - -
CRC-associated lncRNA [125]CRC-associated lncRNA [47] FAP-positive, co-localization with α-SMA Primary tumor - - - ↑ - - -
lncRNA H19 [124]lncRNA H19 [48] - Primary tumor - - - ↑ - - -
TGF-β2 [126]TGF-β2 [49] - Primary tumor - - - ↑ - - Yes [126]
CXCL5 [136]CXCL5 [50] - Primary tumor - - - - ↑ - -
CD70 [138]CD70 [51] Co-localization with α-SMA and FAP Primary tumor - ↑ - - ↑ - Yes [138,141]
CD73 [140]CD73 [52] Co-localization with α-SMA Primary tumor - - - - ↑ - Yes [140]
Endoglin [150]Endoglin [53] Co-localization with α-SMA Primary tumor - - - - - ↑ Yes [150]
BMP2 [151]BMP2 [54] - Primary tumor - ↑ - - - ↑ Yes [151] 3
IL-11 [63]IL-11 [55] FAP-positive Primary tumor - - - - - ↑ -
STC1 [152]STC1 [56] - Primary tumor - ↑ - - - ↑ -

1

Combined with high expression of α-SMA.

2

High expression levels of podoplanin in CAFs were associated with favorable clinical outcomes in CRC patients.

3

Only in patients with SMAD4-deficient tumors. CAF: cancer-associated fibroblast, CRC: colorectal cancer, ECM: extracellular matrix, α-SMA: alpha smooth muscle actin, FAP: fibroblast activation protein, COX-2: cyclooxigenase-2, HIC-5: hydrogen peroxide-inducible clone-5, FGF: fibroblast growth factor, miRNA: microRNA, CD: cluster of differentiation, RAB31: Ras-related protein RAB-31, CLEC3B: C-type lectin domain family 3 member B, SPARC: secreted protein acidic and rich in cysteine, IGF-2: insulin-like growth factor 2, CCBE1: collagen and calcium-binding epidermal growth factor domain 1, lncRNA: long non-coding RNA, TGF- β2: transforming growth factor-β2, CXCL5: C-X-C motif chemokine 5, BMP2: bone morphogenetic protein 2, IL-11: interleukin 11, STC1: stanniocalcin-1. ↑ indicates a tumor-promoting role, ↓ indicates a tumor-suppressing role, = indicates a neutral role (i.e., neither tumor-promoting nor tumor-suppressing).

2.1. Tumor Growth, Invasion, and TME Remodeling

Numerous studies have shown that CAFs can importantly contribute to cancer cell proliferation and invasion [5,6,13,14][5][6][13][14]. In addition, they are also able to affect to tumor progression via remodeling of the ECM or regulation of tumor angiogenesis [106,107,108][57][58][59]. In advanced CRCs, tumor cell proliferation can be promoted by CAFs which express hydrogen peroxide-inducible clone-5 (HIC-5) [25] [109] or Snail-1 [110][28], or CAFs which secrete FGF-1, FGF-3 [111][30], or exosomal circular RNA SLC7A6 [112][24]. Interestingly, some of these CAFs were also found to promote tumor progression via other mechanisms such as enhancing angiogenesis [111][30] or CRC cell invasion [110,112,113][28][24][60]. Another example of a “multifunctional subset” includes Wnt2-expressing CAFs, which can promote CRC cell proliferation and migration [114,115][31][32], facilitate CRC invasion via ECM remodeling [115][32], and increase tumor angiogenesis by secreting several pro-angiogenic factors (e.g., angiopoietin-2 (ANG2), placental growth factor (PGF)) [116][33]. Besides, high levels of Wnt2-expressing CAFs were also associated with an increased risk of cancer metastasis and recurrence in advanced CRCs [114,115][31][32]. A comparable association with worse patient prognosis was found for high expression levels of microRNA-21 [117][36], a factor which is predominantly expressed in CAFs and marks a CAF population which could support CRC cell proliferation and invasion [118,119][34][35].

2.2. Therapeutic Resistance and Immune Regulation

It is well known that CAFs can also facilitate cancer progression by promoting tumor cell resistance to cytotoxic therapies [120,121][61][62]. Several studies have demonstrated that certain CAFs in human CRCs are also able to do so. For example, radiation-induced apoptosis in CRC cells can be reduced by CAFs which express microRNA-31 [122][45] or microRNA-93–5p [123][46]. Moreover, CAFs which express long non-coding RNA (lncRNA) H19 [48] [124] and colorectal cancer-associated lncRNA (CCAL) [125][47], can promote CRC cell stemness and chemoresistance via exosomal transfer of these lncRNAs to tumor cells. TGF-β2 secreting CAFs have also been shown to enhance chemoresistance in a paracrine manner by upregulating glioma-associated oncogene family zinc finger 2 (GLI2) expression in CRC stem cells [126][49]. These CAFs may serve as an important target for prognostic applications, since high expression levels of TGF-β2 were strongly associated with an increased risk of relapse in chemotherapy-treated CRC patients [126][49]. In addition, therapeutic targeting of these CAFs may also become feasible in the (near) future, with several TGF-β inhibitors already being tested in clinical trials [127,128,129,130][63][64][65][66]. Next to supporting therapy resistance, certain CAFs in advanced CRCs can actively contribute to immune evasion of tumor cells (e.g., via aberrant TGF-β signaling [131][67]) and inhibition of anti-tumor immune responses [132,133,134,135][68][69][70][71]. Li et al. reported that CAFs expressing C-X-C motif chemokine 5 (CXCL5) can promote expression of programmed death-ligand 1 (PD-L1) [136][50], an important suppressor of T-cell activity [137][72]. The fact that CAFs are able to produce a defense against T-cells could have important implications for immunotherapies against CRC [132,133,134,135][68][69][70][71]. Moreover, CD70-expressing CAFs were shown to increase the survival of naturally occurring regulatory T-cells [138][51], which are key mediators of immunosuppression [139][73]. CD73-expressing CAFs were also able to enhance immune suppression via adenosine receptor 2A signaling [140][52]. Notably, the abundance of CD70- and CD73-expressing CAFs was significantly associated with a worse prognosis in CRC patients [138,140[51][52][74],141], thereby emphasizing the involvement of immunomodulatory CAFs in CRC progression.

2.3. Metastasis

Currently, metastatic disease remains the major cause of death in CRC patients [153][75]. CAFs can play an important role in mediating CRC metastasis, as summarized by Tommelein et al. [154][76]. Recent work from our group identified several metastasis-promoting CAFs present at the invasive front of primary CRCs, which were also significantly correlated with poor metastasis-free patient survival. These include CAFs which express endoglin [53] [150] or BMP2 [151][54]. Interestingly, BMP2 expression in CAFs seemed to be regulated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cytokine which is overexpressed in CRC cells with a deficiency for mothers against decapentaplegic homolog 4 (SMAD4) [151][54]. These findings provide further support for the idea that the interaction between CRC cells (with a certain mutational status) and CAFs could eventually progress to a tumor-promoting reciprocal loop [155,156,157,158][77][78][79][80]. Other examples of metastasis-promoting CAF populations include IL-11 secreting CAFs, which could activate apoptosis-suppressing programs in metastatic tumor cells [63][55], and stanniocalcin-1 (STC1) expressing CAFs [152][56]. Lastly, next to CAFs in the primary tumor, several studies have suggested that CAFs at the metastatic site, which could originate from resident fibroblasts in remote organs [81][82][83] [159,160,161] or CAFs co-travelling with tumor cells [162[84][85],163], can also contribute to CRC metastasis. For instance, resident liver and lung fibroblasts can induce formation of the pre-metastatic niche via (primary) tumor cell-driven upregulation of pro-inflammatory cytokines such as IL-6 and IL-8 [159,160,161] [81][82][83]. Studies on circulating CAFs originating from primary CRCs have not been conducted yet, but evidence from other cancer types suggests that circulating CAFs may be importantly involved in tumor metastasis and, thus, may serve as useful prognosticators [164][86]. For breast and prostate cancer, it has been shown that circulating CAFs are predominantly found in patients with metastatic disease, and rarely in patients with localized cancer [165,166][87][88].

3. Conclusions

In brief, various tumor-promoting functions (e.g., enhancing tumor invasion, therapy resistance, or metastasis) have been linked to markers expressed by certain CAF populations in advanced CRC. Some of them also seem to serve as promising targets for prognostic or therapeutic applications. However, clinical translation of these findings should be cautiously considered, since it is yet unknown whether these CAF markers demarcate functionally distinct subsets or show overlap with other tumor-promoting or -suppressing CAFs. To enable more precise identification and targeting of “unfavorable” CAFs in advanced CRC, attention needs to be paid to comprehensive characterization and reporting of the subsets being investigated in CAF studies.

 

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