Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-κB-Dependent Manner

Abstract

Cancer-associated fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrate that CAFs also mediate tumor-enhancing inflammation. Using a mouse model of squamous skin carcinogenesis, we found a proinflammatory gene signature in CAFs isolated from dysplastic skin. This signature was maintained in CAFs from subsequent skin carcinomas and was evident in mammary and pancreatic tumors in mice and in cognate human cancers. The inflammatory signature was already activated in CAFs isolated from the initial hyperplastic stage in multistep skin tumorigenesis. CAFs from this pathway promoted macrophage recruitment, neovascularization, and tumor growth, activities that are abolished when NF-kappaB signaling was inhibited. Additionally, we show that normal dermal fibroblasts can be "educated" by carcinoma cells to express proinflammatory genes.

FSP1+ Fibroblasts Promote Skin Carcinogenesis by Maintaining MCP-1-Mediated Macrophage Infiltration and Chronic Inflammation

“…In agreement with this finding, Mueller et al 41 recently reported that stromal fibroblasts could generate an inflammatory microenvironment to promote colorectal liver metastases. In addition, recently Erez et al 42 demonstrated that cancerassociated fibroblasts mediate tumor-enhancing inflammation in a nuclear factor-B-dependent manner.…”

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…CAFs in skin, breast, and pancreatic cancers were found to express a pro-inflammatory gene signature including cyclooxygenase (COX)-2, osteopontin (OPN), CXCL1, CXCL2, IL-6, and IL-1β. In addition, dermal CAFs isolated from a transgenic mouse model of squamous cell carcinogenesis contribute to macrophage recruitment, angiogenesis, and enhanced tumour growth in a nuclear factor-kappa B (NF-κB)-dependent manner [39]. A similar pro-inflammatory gene signature was identified in a subtype of CAFs in inflammation-induced gastric cancer [40].…”

“…IL-1β was expressed by resident immune cells in hyperplastic skin and activated a pro-inflammatory gene signature in dermal CAFs; however, this signature was not induced in CAFs derived from either B-cell-deficient or FcRγ-deficient mice, thus indicating that CAF activation is downstream of humoral immune-mediated activation of inflammatory leukocytes in neoplastic tissue [55]. Thus, B cells produce antibodies that are deposited in neoplastic skin by leaky angiogenic vasculature; these in turn engage FcγR on resident immune cells and induce secretion of IL-1, which activates proinflammatory properties of CAFs [39,54,56].…”

“…Other CAF-derived chemokines were also reported to enhance macrophage recruitment to various tumours: Augsten et al reported that prostate CAFs up-regulate CXCL14 that functioned to promote macrophage migration into prostate cancer xenografts [66]. Inhibition of NF-κB signalling, driving expression of CXCL1 and CXCL2 in skin CAFs, resulted in decreased macrophage infiltration into transplanted skin tumours and reduced tumour growth, indicating a central role for CAFs in facilitating the trafficking of macrophages into tumours [39].…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…While often referred to generically as CAFs, there are evidently a number of distinctive fibroblastic cell types encompassed by this designation, including recruited myofibroblasts expressing smooth muscle actin, and activated (‘reactive’) resident tissue fibroblasts (Pietras and Ostman, 2010). The functionality of CAFs has been demonstrated for example by co‐injection of CAFs together with tumor cells, which enhances tumor growth by promoting ECM synthesis and stiffening, inducing angiogenesis, and recruiting growth‐promoting inflammatory cells such as macrophages (Erez et al., 2010; Kalluri and Zeisberg, 2006; Orimo et al., 2005; Tlsty and Coussens, 2006). CAFs are particularly abundant in certain human cancers, such as PDAC, and in various carcinomas at advanced stages of progression (e.g., breast and colorectal cancer).…”