Cancer-associated fibroblasts play a critical role in cancer cell invasion. To better udnerstand the mechanisms underlying such effects, we establish a heterotypic model of human fibroblasts in co-culture with colon cancer cells, using three-dimensional collagen type-I matrices. Our model will predict that inhibitors directed at this reciprocal molecular and cellular crosstalk will have therapeutic applications for targeting the invasive growth of human primary tumors and their metastatic spread.