Permissive and restrictive influences from breast cancer stroma

Abstract

The turn-over of extracellular matrix is a physiological process, that in normal conditions and in wound healing respond to spatial and temporal regulatory mechanisms, involving several cell-matrix interaction pathways. Profound changes occur both at cellular and extracellular level, during the progression of various forms of invasive carcinomas. Collagen alterations and cellular effects. The ultrastructural and biochemical analyses of the collagenous stroma of invasive ductal breast carcinoma have demonstrated the occurrence of extensive fragmentation of pre-existing collagen fibrils and new deposition of thinner fibrils formed mostly by 1(I)3 homotrimer collagen of type I [1-3], which appears preferentially produced by cancer cells [4]. More recently this collagen has been discovered to be resistant to collagenases, due to less efficient unwinding of homotrimers by MMP-1 [5]. When neoplastic cells are exposed to this collagen in an in vitro system, respond by increasing proliferation and migration rates, and display a proteomic [6,7] and genomic differential profiling versus the control cell cultures. Concurrently, we observed an increase of type V collagen, that when used as a substrate for cell culture, induced opposite effects to that exerted by the homotrimer collagen. A similar restraining effect was obtained when cells were induced to express decorin, a small proteoglycan lysine-rich [8]. Experiments conducted in vivo have revealed that the homotrimer collagen, applied on wound beds of treated guinea pigs, promoted keratynocyte migration into the granulation tissue, therefore confirming its propensity to facilitate local cell invasion and metastasis [9]. Fibrobalst influences. Fibroblasts are the major stromal cells with multiple roles, especially toward both the extracellular matrix and the neighbouring cell population, including neoplastic cells. We recently studied the effects exerted by fibroblasts on cancer cell (8701-BC) proteomics, using a trans-well coculture system. Our results clearly indicated that fibroblasts induce considerable proteomic modulations on 8701-BC, mainly in the cytoskeleton proteins and glycolytic enzymes. Additionally, fibroblast-conditioned medium increased neoplastic cell proliferation and invasion with a concurrent upregulation of the c-Myc oncogene. Collectively these results suggest that fibroblast stimulation may enhance the malignant potential of breast cancer cells in vitro [10]. In conclusion, the present information based on multidisciplinary approaches strongly suggest that the local microenvironment around the primary tumor, emanates influences of opposing signals, which may contribute in directing the neoplastic cells towards