Collagen Linearization within Tumors.

It is now well appreciated that the tumor microenvironment (TME) surrounding primary tumors impacts tumor growth, progression (invasion and migration), and response to therapy. Broadly speaking, the TME is composed of cells (immune cells, activated fibroblasts, adipocytes, endothelial cells), acellular extracellular matrix (ECM), and cytokines or growth factors, some of which are bound or tethered to the ECM proteins. All these compartments undergo significant changes during tumor development and progression.

Tyrosine kinase-independent actions of DDR2 in tumor cells and cancer-associated fibroblasts influence tumor invasion, migration and metastasis.

Both tumor cell-intrinsic signals and tumor cell-extrinsic signals from cells within the tumor microenvironment influence tumor cell dissemination and metastasis. The fibrillar collagen receptor tyrosine kinase (RTK) discoidin domain receptor 2 (DDR2) is essential for breast cancer metastasis in mouse models, and high expression of DDR2 in tumor and tumor stromal cells is strongly associated with poorer clinical outcomes. DDR2 tyrosine kinase activity has been hypothesized to be required for the metastatic activity of DDR2; however, inhibition of DDR2 tyrosine kinase activity, along with that of other RTKs, has failed to provide clinically relevant responses in metastatic patients.

Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells.

Background: The development and progression of estrogen receptor alpha positive (ERα+) breast cancer has been linked epidemiologically to prolactin. However, activation of the canonical mediator of prolactin, STAT5, is associated with more differentiated cancers and better prognoses. We have reported that density/stiffness of the extracellular matrix potently modulates the repertoire of prolactin signals in human ERα + breast cancer cells in vitro: stiff matrices shift the balance from the Janus kinase (JAK)2/STAT5 cascade toward pro-tumor progressive extracellular regulated kinase (ERK)1/2 signals, driving invasion.

Prolactin signaling through focal adhesion complexes is amplified by stiff extracellular matrices in breast cancer cells.

Estrogen receptor α positive (ERα+) breast cancer accounts for most breast cancer deaths. Both prolactin (PRL) and extracellular matrix (ECM) stiffness/density have been implicated in metastatic progression of this disease. We previously demonstrated that these factors cooperate to fuel processes involved in cancer progression.

Dense collagen-I matrices enhance pro-tumorigenic estrogen-prolactin crosstalk in MCF-7 and T47D breast cancer cells.

Breast cancers that express estrogen receptor alpha (ERα+) constitute the majority of breast tumors. Estrogen is a major driver of their growth, and targeting ER-mediated signals is a largely successful primary therapeutic strategy. Nonetheless, ERα+ tumors also result in the most breast cancer mortalities.

Stiff collagen matrices increase tumorigenic prolactin signaling in breast cancer cells.

Clinically, circulating prolactin levels and density of the extracellular matrix (ECM) are individual risk factors for breast cancer. As tumors develop, the surrounding stroma responds with increased deposition and cross-linking of the collagen matrix (desmoplasia). In mouse models, prolactin promotes mammary carcinomas that resemble luminal breast cancers in women, and increased collagen density promotes tumor metastasis and progression.