CD90⁺ stromal cells are the major source of IL‐6, which supports cancer stem‐like cells and inflammation in colorectal cancer

Abstract

IL-6 is a pleiotropic cytokine increased in CRC and known to directly promote tumor growth. Colonic myofibroblasts/fibroblasts (CMFs or stromal cells) are CD90+ innate immune cells representing up to 30% of normal colonic mucosal lamina propria cells. They are expanded in CRC tumor stroma, where they also known as a cancer associated fibroblasts (CAFs). Cells of mesenchymal origin, such as normal myofibroblasts/fibroblasts, are known to secrete IL-6; however their contribution to the increase in IL-6 in CRC and to tumor-promoting inflammation is not well defined. Using in situ, ex vivo and co-culture analyses we have demonstrated that the number of IL-6 producing CMFs is increased in CRC (C-CMFs) and they represent the major source of IL-6 in T2-T3 CRC tumors. Expression of stem cell markers-aldehyde dehydrogenase (ALDH) and LGR5- was significantly up-regulated in colon cancer cells (SW480, Caco-2 or HT29) cultured in the presence of conditioned medium from tumor isolated C-CMFs in an IL-6 dependent manner. C-CMF and its derived condition medium, but not normal CMF isolated from syngeneic normal colons, induced differentiation of tumor promoting inflammatory Th17 cell responses in an IL-6 dependent manner. Our study suggests that CD90+ fibroblasts/myofibroblasts may be the major source of IL-6 in T2-T3 CRC tumors, which supports the stemness of tumor cells and induces an immune adaptive inflammatory response (a.k.a. Th17) favoring tumor growth. Taken together our data supports the notion that IL-6 producing CAFs (a.k.a. C-CMFs) may provide a useful target for treating or preventing CRCs.

Signal Transduction and Activator of Transcription-3 (STAT3) in Patients with Colorectal Cancer: Associations with the Phenotypic Features of the Tumor and Host

“…On multivariate survival analysis (Table 5) Although failing to reach statistical significance, the density of tumour-associated stroma, as measured by TSP, appeared to be associated with pSTAT3 expression. Given that an increase in TSP primarily reflects an increased population of cancer-associated fibroblasts within the tumour microenvironment, this would further support the importance of IL-6 secretion by fibroblasts in the activation of the JAK/STAT3 pathway in tumour cells (14,15).…”

“…Circulating IL-6 is commonly elevated in a number of cancers, including colorectal cancer (11)(12)(13), and is the predominant stimulus for the hepatic synthesis of acute phase proteins, including CRP (6). Cancer-associated fibroblasts and inflammatory cells contribute to high levels of IL-6 within the tumour microenvironment (14,15), with subsequent tumour cell activation of the soluble IL-6 receptor/ glycoprotein 130 complex (16). Interleukin-6 trans-signalling regulates JAK activity within the tumour cell to promote phosphorylation of the tyrosine 705 residue of STAT3.…”

“…Interleukin-6 trans-signalling regulates JAK activity within the tumour cell to promote phosphorylation of the tyrosine 705 residue of STAT3. Phosphorylated STAT3 (pSTAT3) translocates to the nucleus where it is a key transcription factor for numerous T h 2-type cytokines, including IL-6 (12,14), which promote a pro-tumour, immunosuppressive environment and attenuate host anti-tumour immune responses (15,17). Indeed, given its role in not only de-regulation of the host anti-tumour immune response, but also in orchestrating numerous pro-oncogenic processes (15,18,19), it is not surprising that STAT3 expression and activation has previously been associated with reduced survival in a number of gastrointestinal cancers, including colorectal cancer (20).…”

Old fibroblasts secrete inflammatory cytokines that drive variability in reprogramming efficiency and may affect wound healing between old individuals

“…3b, Extended Table 4a-c). THY1 has been associated with populations of fibroblasts with activated features in tissues 56,57 and with secretion of proinflammatory cytokines in the context of diseases 58,59 . FACS analysis using antibodies to THY1 and to the pan-fibroblast marker PDGFRα 60 confirmed that old fibroblast cultures in general contained a higher proportion of THY1-positive/PDGFRα-positive cells (hereafter termed THY1+ cells) (Fig.…”

Map3k2-Regulated Intestinal Stromal Cells (MRISC) Define a Distinct Sub-cryptic Stem Cell Niche for Damage Induced Wnt Agonist R-spondin1 Production

“…Several studies have now suggested that CD90 + IMSC may be crucial regulators of gut homeostasis (Huynh et al, 2016; Karpus et al, 2019; Kinchen et al, 2018; Powell et al, 2011; Roulis et al, 2014). However, recent efforts to understand the heterogeneity and function of ISMC using single-cell RNA sequencing (scRNA-seq) and lineage tracing techniques have revealed the existence of multiple functionally distinct subsets (Kinchen et al, 2018; Nanki et al, 2018), many of which produce soluble factors and cytokines likely capable of modulating gut homeostasis and epithelial integrity (Han et al, 2018; Kinchen et al, 2018; Shoshkes-Carmel et al, 2018; Thomson et al, 2018).…”