Stromal fibroblasts in cancer initiation and progression

Abstract

It is widely accepted that the development of carcinoma--the most common form of human cancer--is due to the accumulation of somatic mutations in epithelial cells. The behaviour of carcinomas is also influenced by the tumour microenvironment, which includes extracellular matrix, blood vasculature, inflammatory cells and fibroblasts. Recent studies reveal that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated. These new findings have important therapeutic implications.

Figure 1

The stroma associated with normal mammary gland differs profoundly from stroma associated with a mammary carcinoma. (A) Note that the normal mammary gland has sparse connective tissue (arrow) surrounding the duct and abundant adipose tissue (*). (B) The carcinoma contains abundant connective likely as a result of growth factor production by the carcinogenic environment. Note the dense collagen bundles associated with fibroblasts (*) and the numerous small blood vessels and capillaries (arrow heads). The carcinoma cells form aberrant gland structures (green arrows) or grow in cords without gland formation (black arrow).

Figure 2. Epithelia can be reactive to a changing stromal environment

(A) Homeostatic interactions between the epithelia and fibroblasts are maintained through positive and negative signals influencing the proliferation and differentiation of both the stroma and epithelia. (B) When singalling by a suppressive growth factor (TGF-β) to the stromal fibroblasts is lost (red starburst), it leads to elevated fibroblast proliferation. Resulting paracrine factors (e.g., HGF) and potential modifications in the ECM can stimulate the proliferation and transformation of epithelial cells in some tissues in vivo.