Tumour invasion and metastasis are not cell cancer cell-autonomous conditions, but involve complex heterotypic multicellular interactions. Bone marrow derived mesenchymal stem cells migrate to primary colorectal cancers and are precursors of carcinoma-associated fibroblasts, which, in turn, drive tumour progression. The molecular mechanisms of how these supporting host cells modulate colorectal cancer progression are largely unknown and understanding them is of profound clinical importance. Our research group recently discovered that bone marrow mesenchymal stem cells stimulate invasion, survival and tumorigenesis of colorectal cancer cells through the release of soluble factors. Soluble neuregulin 1 secreted by bone marrow mesenchymal stem cells was responsible for the observed effects, and signalled through HER2/HER3-dependent activation of the PI3K/AKT/BAD pathway in colorectal cancer cells. Immunohistochemical data demonstrated that transmembrane neuregulin 1 is expressed in carcinoma-associated fibroblasts in clinical colorectal cancer specimens, with the strongest expression in the immediate vicinity of infiltrative HER2/HER3 expressing cancer cells. High transmembrane neuregulin 1 expression levels were associated with advanced tumour stage, invasion depth and decreased five-year progression free survival. These results indicate that stromal transmembrane neuregulin 1 may serve as a novel prognostic marker for colorectal cancer. Strategies that disable this mesenchymal-epithelial interaction may be of therapeutic value for colorectal cancer.