Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression

Abstract

Tumours are highly complex tissues composed of carcinoma cells and surrounding stroma, which is constructed by various different types of mesenchymal cells and an extracellular matrix (ECM). Carcinoma-associated fibroblasts (CAFs), which consist of both fibroblasts and myofibroblasts, are frequently observed in the stroma of human carcinomas, and their presence in large numbers is often associated with the development of high-grade malignancies and poor prognoses. Moreover, in human tumour xenograft models, CAFs extracted from the tumour are more capable of promoting tumour growth through their interactions with carcinoma cells when compared to those isolated from non-cancerous stroma. Taken together, these observations strongly suggest that CAFs actively contribute to tumour progression. In this review we highlight the emerging roles of these cells in promoting tumourigenesis, and we discuss the molecular mechanisms underlying their tumour-promoting capabilities and their cellular origin.

Fig. 1

Large numbers of myofibroblasts exist in the stroma of human breast tumour. Paraffin sections were prepared from human non-neoplastic breast tissue (a and c) or invasive breast cancer tissue (b and d) dissected from the same individual. These sections were stained with hematoxylin and eosin (H&E) (c and d) or immunostained with an anti-α-SMA antibody (a and b). α-SMA-positive myoepithelial cells surrounding epithelial cells (an arrow in a) are observed in normal tissue (a), whilst α-SMA-positive myofibroblasts (arrows in b) are only found in the tumour-associated stroma (b) (from Ref. [22]).

Fig. 2

Four alternative models for cellular origins and evolution of myofibroblasts in the stroma of tumour. (1) Transdifferentiation into myofibroblasts. Populations of residual mesenchymal cells (e.g., stromal fibroblasts) might transdifferentiate into myofibroblasts without acquiring any significant genetic alterations; (2) differentiation into myofibroblasts. Stromal myofibroblasts are recruited from specialised circulating bone marrow-derived progenitor cell types, such as fibrocytes and MSCs, which differentiate into myofibroblasts within the tumour stroma; (3) selection of pre-existing myofibroblasts. A small population of pre-existing myofibroblasts may be clonally expanded in the tumour without acquiring any further phenotypic alterations; (4) selection of genetically altered fibroblasts. Acquisition of genetic alterations (e.g., p53 loss) may allow for the clonal selection from a small population of fibroblasts or progenitors that have undergone such alterations. The resulting fibroblasts may or may not then differentiate into myofibroblasts.

Fig. 3

Diverse tumour-promoting affects of CAFs. Carcinoma cell-derived TGF-β and PDGFs play central role to induce and maintain CAF myofibroblasts within the stroma of tumour. CAF-derived SDF-1 , FGF2 and VEGF boost angiogenesis. SDF-1 , IGF2 , HGF , Gremlin-1 , and SFRP-1 also stimulate tumour cell proliferation. Moreover, CAFs enhance tumour invasion through their secretion of TGF-β, tenascin-C , tenascin-W , HGF , and matrix metalloproteinases (MMPs). Furthermore, CAF-produced SFRP1 serves as an anti-apoptotic factor. Taken together, CAFs could promote tumour progression in several aspects through their ability to produce elevated levels of various growth factors, cytokines, ECM proteins and MMPs.