Crosstalk between breast cancer stem cells and metastatic niche: emerging molecular metastasis pathway?

Abstract

Metastatic colonization represents the final step of metastasis, and is the major cause of cancer mortality. Metastasis as an "inefficient" process requires the right population of tumor cells in a suitable microenvironment to form secondary tumors. Cancer stem cells are the only capable population of tumor cells to progress to overt metastasis. On the other hand, the occurrence of appropriate microenvironmental conditions within the target tissue would be critical for metastasis formation. Metastatic niche seems to be the specialized microenvironment to support tumor initiating cells at the distant organ. Master regulators not only determine cancer stem cell state, but also may have regulatory roles in metastatic niche elements. Meanwhile, both cancer stem cell and metastatic niche may function like two sides of the metastatic coin. Hypoxia inducible factors have multiple roles in regulation of both sides of this coin. TGF-β superfamily, also, have been considered as master regulators of epithelial to mesenchymal transition and metastasis and may play crucial roles in regulation of metastatic niche as well. In this regard, we hypothesize the presence of a possible emerging molecular pathway in the biological process of breast cancer metastasis. In this process, non-Smad TGF-β-induced metastasis connects cancer stem cell and metastatic niche formation through a central path, "Metastasis Pathway".

SLUG and SOX9 Cooperatively Regulate Tumor Initiating Niche Factors in Breast Cancer

“…So by considering above-mentioned facts, we hypothesized that there might be a regulatory connection between these major players and factors in breast cancer metastasis [8]. Having these seminal previous works as backbone, in this study we show that expression of TNC and POSTN is correlated and consistent with that of SLUG and SOX9, when the latter are simultaneously expressed.…”

“…On the other hand, SLUG can induce TGF-β3 [10] which together may propose a molecular cascade with TGF-β, WNT and NOTCH interfaces. These signaling pathways are crucial players in the induction and maintenance of TICs and EMT-TFs as autocrine reinforcing signals in metastasis and also stemness [8,11].…”

Breast cancer lung metastasis: Molecular biology and therapeutic implications

“…[133][134][135][136] Ye et al used the 4T1 syngeneic mouse model to demonstrate that TGF-b participates in creating a lung pre-metastatic microenvironment by modulating certain inflammatory cytokines (S100A8/A9) and growth factors (VEGF, Angpt2). 137 Park et al found that IN-1130, a novel TGFb¡1 receptor kinase (ALK5) inhibitor, could suppress lung metastasis in the 4T1 breast cancer orthotopic xenograft mouse model.…”

TGFβ modulates inflammatory cytokines and growth factors to create premetastatic microenvironment and stimulate lung metastasis

“…In our laboratory, we have shown that TGFb permits advanced breast cancer cell lines 4T1 and MDA-MB-231 to acquire invasive and metastatic properties (Ye et al 2013). Moreover, TGFb also influences stromal, immune, vascular, and cancer stem cells to control features of the microenvironment (Padua et al 2008;Hembruff et al 2010;Drabsch and ten Dijke 2011;Fazilaty et al 2013). …”