System-Wide Analysis Reveals a Complex Network of Tumor-Fibroblast Interactions Involved in Tumorigenicity

Abstract

Many fibroblast-secreted proteins promote tumorigenicity, and several factors secreted by cancer cells have in turn been proposed to induce these proteins. It is not clear whether there are single dominant pathways underlying these interactions or whether they involve multiple pathways acting in parallel. Here, we identified 42 fibroblast-secreted factors induced by breast cancer cells using comparative genomic analysis. To determine what fraction was active in promoting tumorigenicity, we chose five representative fibroblast-secreted factors for in vivo analysis. We found that the majority (three out of five) played equally major roles in promoting tumorigenicity, and intriguingly, each one had distinct effects on the tumor microenvironment. Specifically, fibroblast-secreted amphiregulin promoted breast cancer cell survival, whereas the chemokine CCL7 stimulated tumor cell proliferation while CCL2 promoted innate immune cell infiltration and angiogenesis. The other two factors tested had minor (CCL8) or minimally (STC1) significant effects on the ability of fibroblasts to promote tumor growth. The importance of parallel interactions between fibroblasts and cancer cells was tested by simultaneously targeting fibroblast-secreted amphiregulin and the CCL7 receptor on cancer cells, and this was significantly more efficacious than blocking either pathway alone. We further explored the concept of parallel interactions by testing the extent to which induction of critical fibroblast-secreted proteins could be achieved by single, previously identified, factors produced by breast cancer cells. We found that although single factors could induce a subset of genes, even combinations of factors failed to induce the full repertoire of functionally important fibroblast-secreted proteins. Together, these results delineate a complex network of tumor-fibroblast interactions that act in parallel to promote tumorigenicity and suggest that effective anti-stromal therapeutic strategies will need to be multi-targeted.

Extracellular vesicle-mediated transfer of processed and functional RNY5 RNA

“…These results appear to indicate that not all cultured cells are equally sensitive. Recent reports indicate that tumor-fibroblast interactions act in parallel to promote tumorigenicity and not all associated primary fibroblast cells may be involved in this cooperational activity (Rajaram et al 2013). One testable hypothesis in future studies is to determine whether the surviving primary cells after treatment with either cancer cell EVs or the 31-nt processed product continue to fail to respond to the exposure of the 31 nt or EVs or if they do provide support for tumor growth.…”

Roles of the Cyclooxygenase 2 Matrix Metalloproteinase 1 Pathway in Brain Metastasis of Breast Cancer

“…Similarly, CCL7 was found to be positively correlated to invasion and metastasis and patient survival of gastric cancer (57). More recently, Rajaram et al (34) found that fibroblast-secreted CCL7 is capable of promoting proliferation of breast cancer cells. CCL7 appears to activate G-protein through its receptor and following the MAPK pathway (58), which is known to play a critical role in maintaining stemness of embryonic stem cells (59).…”

Illuminating breast cancer invasion: diverse roles for cell–cell interactions

“…Cumulatively, these paracrine signals create spatially distinct tumor microenvironments in vivo that modulate cancer cell behaviors locally [33]. In the complex tissue environment in vivo , bidirectional signaling networks also emerge from paracrine interactions between cells [19,34–36]. Cancer cells release soluble factors that regulate the behaviors of the cells around them, creating opportunities for signaling feedback.…”