Abstract
IntroductionAccumulating evidence suggests that fibroblasts play a pivotal role in promoting the growth of breast cancer cells. The objective of the present study was to characterize and validate an in vitro model of the interaction between small numbers of human breast cancer cells and human fibroblasts.MethodsWe measured the clonogenic growth of small numbers of human breast cancer cells co-cultured in direct contact with serum-activated, normal human fibroblasts. Using DNA microarrays, we also characterized the gene expression profile of the serum-activated fibroblasts. In order to validate the in vivo relevance of our experiments, we then analyzed clinical samples of metastatic breast cancer for the presence of myofibroblasts expressing α-smooth muscle actin.ResultsClonogenic growth of human breast cancer cells obtained directly from in situ and invasive tumors was dramatically and consistently enhanced when the tumor cells were co-cultured in direct contact with serum-activated fibroblasts. This effect was abolished when the cells were co-cultured in transwells separated by permeable inserts. The fibroblasts in our experimental model exhibited a gene expression signature characteristic of 'serum response' (i.e. myofibroblasts). Immunostaining of human samples of metastatic breast cancer tissue confirmed that myofibroblasts are in direct contact with breast cancer cells.ConclusionSerum-activated fibroblasts promote the clonogenic growth of human breast cancer cells in vitro through a mechanism that involves direct physical contact between the cells. This model shares many important molecular and phenotypic similarities with the fibroblasts that are naturally found in breast cancers.
Highlights
Accumulating evidence suggests that fibroblasts play a pivotal role in promoting the growth of breast cancer cells
Clonogenic growth of human breast cancer cells obtained directly from in situ and invasive tumors was Keywords: fibroblasts, metastatic, microarrays, myofibroblasts, serum dramatically and consistently enhanced when the tumor cells were co-cultured in direct contact with serum-activated fibroblasts
Immunostaining of human samples of metastatic breast cancer tissue confirmed that myofibroblasts are in direct contact with breast cancer cells
Summary
Accumulating evidence suggests that fibroblasts play a pivotal role in promoting the growth of breast cancer cells. Tumorassociated myofibroblasts are believed to originate from normal fibroblasts and are similar or identical to the myofibroblasts found in healing wounds [1] They are largely responsible for the desmoplasia that is characteristically present in carcinomas because they secrete large amounts of collagen and other extracellular matrix proteins. An orthotopic xenograft model was created in mice in which both the stromal and epithelial components of the reconstructed mammary gland are of human origin [10] This complex model again underscored the critical role played by heterotypic interactions in human breast carcinogenesis. Of any previous reports of studies investigating the ability of fibroblasts to promote the clonogenic growth of small numbers of primary breast cancer cells in vitro
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