Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization

Abstract

Tumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but underlying mechanisms remain elusive. To evaluate CAM-DR as target for sensitization strategies, we analyzed signaling pathways in human estrogen-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells by western blot, proteome profiler array and TOP-flash assay in presence of COL1. β1-Integrins, known to bind COL1, appear as key for mediating COL1-related resistance in both cell lines that primarily follows FAK/PI3K/AKT pathway in MCF-7, and MAPK pathway in MDA-MB-231 cells. Notably, pCREB is highly elevated in both cell lines. Consequently, blocking these pathways sensitizes the cells evidently to CDDP and MX treatment. Wnt signaling is not relevant in this context. A β1-integrin knockdown of MCF-7 cells (MCF-7-β1-kd) reveals a signaling shift from FAK/PI3K/AKT to MAPK pathway, thus CREB emerges as a promising primary target for sensitization in MDA-MB-231, and secondary target in MCF-7 cells. Concluding, we provide evidence for importance of CAM-DR in breast cancer cells and identify intracellular signaling pathways as targets to sensitize cells for cytotoxicity treatment regimes.

The Impact of Integrin-Mediated Matrix Adhesion on Cisplatin Resistance of W1 Ovarian Cancer Cells

“…ILK expression is clearly upregulated in W1 cells upon COL1 binding, but more impressively, ILK inhibition using a non-toxic concentration of the inhibitor cdp22 significantly sensitized the W1 cells for cisplatin cytotoxicity. This is comparable to recent studies in other tumor entities showing an interference with integrin signaling as promising targets for sensitization against CAM-DR [14].…”

“…Furthermore, CAM-DR emerges as an independent process adding to the resistance phenomena already developed in ovarian cancer cells, which has not been shown before. Although the resistance rate, i.e., the shift to higher EC 50 values of cytostatic drugs by matrix binding of cells is expected to be moderate or even low in terms of the non-genetic nature [14,15], the duplication of cisplatin EC 50 values in both W1 and W1CR cells shown here, is remarkable. However, although these findings emphasize CAM-DR in its relevance, our present data have to be discussed and interpreted cautiously, for other ovarian cancer cells, also with respect to other types of ECM matrices, other environmental components, or antineoplastic drugs.…”

“…Integrins, the heterodimeric adhesion that molecules possess, depending on their subunit composition, the capability to bind ECM components. Since integrin binding activity does not only regulate a physical cell embedding into an ECM, but also activates specific signaling pathways, integrins appear as relevant candidates for mediating CAM-DR. We have recently shown that the β1-integrin (ITGB1) plays a crucial role in breast cancer and melanoma cell lines, forming a resistant state against cytostatic drugs when cells bind to ECM components [14,15].…”

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…Especially under hypoxic conditions, CAFs produce high levels of TGFβ, which induces stem celllike properties in tumor cells including increased resistance to chemotherapy (Tang et al, 2018). Finally, the complex ECM produced by CAFs interferes with therapeutic response by forming a shielding barrier and providing prompts for protective signaling, e.g., via interaction with integrins and cadherins (Eke et al, 2010;Naci et al, 2012;McGrail et al, 2015;Jakubzig et al, 2018;Naik et al, 2018). Based on these observations, it should be possible to significantly improve drug distribution and response to therapy by depleting CAFs in the tumor stroma.…”

The role of collagen in cancer: from bench to bedside

“…Specifically, different collagen types exhibit distinct treatment resistances. COLI induced resistance to drugs, such as cisplatin and mitoxantrone, by activating β1 integrin followed by the FAK/PI3K/AKT pathway in ER-positive cancer cells, the MAPK pathway in triple-negative cancer cells, the coexpression of LOX with COL1A2 in ovarian cancer, and the TGF-β1/Smad3-mediated expression of COLI and COLIII in bromocriptine-resistant prolactinoma cells [182][183][184]. Other mechanisms of drug resistance include COLI-induced tau upregulation, resulting in paclitaxel resistance in ovarian carcinoma [185].…”