The fibroblast Tiam1-osteopontin pathway modulates breast cancer invasion and metastasis

Abstract

BackgroundThe tumor microenvironment has complex effects in cancer pathophysiology that are not fully understood. Most cancer therapies are directed against malignant cells specifically, leaving pro-malignant signals from the microenvironment unaddressed. Defining specific mechanisms by which the tumor microenvironment contributes to breast cancer metastasis may lead to new therapeutic approaches against advanced breast cancer.MethodsWe use a novel method for manipulating three-dimensional mixed cell co-cultures, along with studies in mouse xenograft models of human breast cancer and a histologic study of human breast cancer samples, to investigate how breast cancer-associated fibroblasts affect the malignant behaviors of breast cancer cells.ResultsAltering fibroblast Tiam1 expression induces changes in invasion, migration, epithelial-mesenchymal transition, and cancer stem cell characteristics in associated breast cancer cells. These changes are both dependent on fibroblast secretion of osteopontin and also long-lasting even after cancer cell dissociation from the fibroblasts, indicating a novel Tiam1-osteopontin pathway in breast cancer-associated fibroblasts. Notably, inhibition of fibroblast osteopontin with low doses of a novel small molecule prevents lung metastasis in a mouse model of human breast cancer metastasis. Moreover, fibroblast expression patterns of Tiam1 and osteopontin in human breast cancers show converse changes correlating with invasion, supporting the hypothesis that this pathway in tumor-associated fibroblasts regulates breast cancer invasiveness in human disease and is thus clinically relevant.ConclusionsThese findings suggest a new therapeutic paradigm for preventing breast cancer metastasis. Pro-malignant signals from the tumor microenvironment with long-lasting effects on associated cancer cells may perpetuate the metastatic potential of developing cancers. Inhibition of these microenvironment signals represents a new therapeutic strategy against cancer metastasis that enables targeting of stromal cells with less genetic plasticity than associated cancer cells and opens new avenues for investigation of novel therapeutic targets and agents.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0674-8) contains supplementary material, which is available to authorized users.

ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma

“…Interestingly, downregulation of the RacGEF TIAM1 by mutant BRAF was shown to enhance invasion of human melanoma cells (46). Although PREX1 was not examined in that particular study, PREX1 has consistently demonstrated a positive role in invasion (6,17,47), whereas TIAM1 can be either a positive or a negative regulator of this process (1,46,48-50). Thus, the relative input from different upstream activators of RAC1 can have a profound influence on melanoma invasion.…”

Breast cancer lung metastasis: Molecular biology and therapeutic implications

“…A report showed that CAFs express Tiam1 and osteopontin in human breast cancer and regulate metastasis of breast cancer. 157 Moreover, expression of platelet-derived growth factor receptor b (PDGFRb), a CAFs associated protein is significantly associated with lung metastasis in breast cancer. 158 CAFs could also regulate TGF-b ligands, thereby promoting primary tumor growth.…”

Identifying progression predictors of breast ductal carcinoma in situ

“…Furthermore, secretion of the chemokine CXCL12 by CAFs may promote angiogenesis and increase cancer cell proliferation through interactions with CXCR4 expressed by breast tumour cells 86. Using an integrative strategy with 3D (three dimension) cell culture of tumour spheroid, clinical samples and xenograft mouse models, Xu et al 17 demonstrated that the T-cell lymphoma invasion and metastasis 1—osteopontin pathway in CAF mediates invasive behaviour of associated breast cancer cells and that inhibition of this interaction could prevent metastasis of breast cancer cells in a murine model. Intriguingly, the changes to breast cancer cell behaviour in vitro persisted following the removal of CAFs, highlighting the potential for profound and lasting impact of intercellular interactions between stromal and tumour cells to affect clinical outcome (table 1).…”

“…The percentage of IDCs associated with DCIS varies by the molecular subtype, with human epidermal growth factor receptor 2-positive and luminal IDC being more frequently associated with DCIS than basal-like breast cancers;17 however, neither molecular subtype nor histological features/grades are consistent or reproducible predictors of DCIS behaviour. Two schools of thought have thus emerged on the progression of DCIS to IDC, that is, DCIS becomes invasive as a result of intrinsic factors, namely genetic aberrations of the neoplastic cells or alternatively that extrinsic factors within the microenvironment or tumour stroma drive DCIS progression, independent of or in conjunction with genetic changes within neoplastic cells 1.…”