Carcinoma‐associated fibroblasts: Non‐neoplastic tumour‐promoting mesenchymal cells

Abstract

Cancerous stroma coevolves alongside tumour progression, thereby promoting the malignant conversion of epithelial carcinoma cells. To date, an abundance of data have supported crucial roles of the tumour microenvironment (TME) in providing cancer cells with proliferative, migratory, survival and invasive propensities favouring the processes of tumourigenesis. The cancerous reactive stroma is frequently populated by a large number of myofibroblasts (MFs), which are activated, non-transformed fibroblasts expressing α-smooth muscle actin (α-SMA). MFs together with non-MF cells present in the tumour-associated stroma are collectively referred to as carcinoma-associated fibroblasts (CAFs), one of the major stromal cell types recognised in various human carcinomas. Recruitment of fibroblasts and/or their progenitors to a tumour mass and their subsequent transdifferentiation into MFs, as well as ongoing maintenance of their activated state, are believed to be essential processes facilitating tumour progression. However, the complex networks of signalling pathways mediating the phenotypic conversion into CAFs, as well as those underlying their tumour-promoting interactions with other tumour-constituting cells, have yet to be fully explored. Histopathological confirmation of the presence of large numbers of CAF MFs within TME and their altered gene expression profiles are known to be associated with disease progression and to serve as independent negative prognostic factors for a wide range of tumour types. In this review, we examine the current evidence shedding light on the emerging roles of tumour-promoting CAFs, cells that are pivotal for epithelial cancer development and progression, and discuss the therapeutic potential of targeting these cells.

Common fibroid-associated genes are differentially expressed in phenotypically dissimilar cell populations isolated from within human fibroids and myometrium

“…Members of the transforming growth factor b (TGFB) family participate in tumour microenvironment signalling, playing a major role in fibroblast-associated tumorigenesis. Members of the TGFB family can elicit tumour-promoting effects in a paracrine manner by triggering fibroblast differentiation and desmoplastic responses from neighbouring mesenchymal cells within a tumour (reviewed by Elenbaas & Weinberg (2001) and Polanska & Orimo (2013)). Activation of the retinoic acid (RA) pathway significantly reduces growth and extracellular matrix composition of uterine fibroid cells via regulation of the TGFB pathway (Malik et al 2008).…”

Le stroma tumoral

“…Ainsi, les CAF peuvent tout d'abord provenir de la multiplication de fibroblastes résidents. Plusieurs autres types cellulaires d'origine mésenchymateuse peuvent être mis à contribution, dont notamment les péricytes, les préadipocytes voire les adipocytes, les fibroblastes sénescents, des cellules souches, ou encore des cellules issues de la moelle osseuse [8,11,12]. Ces différentes provenances pourraient expliquer les variations phénotypiques du profil moléculaire des CAF.…”

“…Ces différentes provenances pourraient expliquer les variations phénotypiques du profil moléculaire des CAF. En effet, de nombreux facteurs sont exprimés différentiellement dans les CAF par rapport aux fibroblastes des tissus normaux, et jouent un rôle dans la progression tumorale (Figure 2) [11,12]. D'un point de vue fonctionnel, les CAF influencent le devenir des cellules cancéreuses [1][2][3].…”

Bone mesenchymal stem cells differentiate into myofibroblasts in the tumor microenvironment

“…Myofibroblasts constitute the bulk of the cancer stroma; these cells are activated, non-transformed fibroblasts that express α-smooth muscle actin (α-SMA) (2) and are observable in various human carcinomas (3). Myofibroblasts are able to promote cancer initiation, angiogenesis, invasion and metastasis (4) by secretion of elevated levels of growth factors, chemokines and matrix metalloproteinases (MMPS) (5,6).…”