Permissive and restrictive influences from breast cancer stroma

The turn-over of extracellular matrix is a physiological process, that in normal conditions and in wound healingrespond 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 invasivecarcinomas.Collagen alterations and cellular effects. Theultrastructural and biochemical analyses of the collagenousstroma of invasive ductal breast carcinoma have demonstratedthe occurrence of extensive fragmentation of pre-existingcollagen fibrils and new deposition of thinner fibrils formedmostly by 1(I)3 homotrimer collagen of type I [1-3], whichappears preferentially produced by cancer cells [4]. Morerecently this collagen has been discovered to be resistant tocollagenases, due to less efficient unwinding of homotrimers byMMP-1 [5].When neoplastic cells are exposed to this collagen in an invitro system, respond by increasing proliferation and migrationrates, and display a proteomic [6,7] and genomic differentialprofiling versus the control cell cultures. Concurrently, weobserved an increase of type V collagen, that when used as a substrate for cell culture, induced opposite effects tothat exerted by the homotrimer collagen. A similar restraining effect was obtained when cells were induced toexpress decorin, a small proteoglycan lysine-rich [8]. Experiments conducted in vivo have revealed that thehomotrimer collagen, applied on wound beds of treated guinea pigs, promoted keratynocyte migration into thegranulation 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 theextracellular matrix and the neighbouring cell population, including neoplastic cells. We recently studied the effectsexerted by fibroblasts on cancer cell (8701-BC) proteomics, using a trans-well coculture system. Our results clearlyindicated that fibroblasts induce considerable proteomic modulations on 8701-BC, mainly in the cytoskeletonproteins and glycolytic enzymes. Additionally, fibroblast-conditioned medium increased neoplastic cell proliferationand invasion with a concurrent upregulation of the c-Myc oncogene. Collectively these results suggest that fibroblaststimulation 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