Cell Adhesion Mediated Drug Resistance (CAM-DR): Role of Integrins and Resistance to Apoptosis in Human Myeloma Cell Lines

Abstract

Integrin-mediated adhesion influences cell survival and may prevent programmed cell death. Little is known about how drug-sensitive tumor cell lines survive initial exposures to cytotoxic drugs and eventually select for drug-resistant populations. Factors that allow for cell survival following acute cytotoxic drug exposure may differ from drug resistance mechanisms selected for by chronic drug exposure. We show here that drug-sensitive 8226 human myeloma cells, demonstrated to express both VLA-4 (4β1) and VLA-5 (5β1) integrin fibronectin (FN) receptors, are relatively resistant to the apoptotic effects of doxorubicin and melphalan when pre-adhered to FN and compared with cells grown in suspension. This cell adhesion mediated drug resistance, or CAM-DR, was not due to reduced drug accumulation or upregulation of anti-apoptotic Bcl-2 family members. As determined by flow cytometry, myeloma cell lines selected for drug resistance, with either doxorubicin or melphalan, overexpress VLA-4. Functional assays revealed a significant increase in 4-mediated cell adhesion in both drug-resistant variants compared with the drug-sensitive parent line. When removed from selection pressure, drug-resistant cell lines reverted to a drug sensitive and 4-low phenotype. Whether VLA-4–mediated FN adhesion offers a survival advantage over VLA-5–mediated adhesion remains to be determined. In conclusion, we have demonstrated that FN-mediated adhesion confers a survival advantage for myeloma cells acutely exposed to cytotoxic drugs by inhibiting drug-induced apoptosis. This finding may explain how some cells survive initial drug exposure and eventually express classical mechanisms of drug resistance such as MDR1 overexpression.

Enhancing the R‐ISS classification of newly diagnosed multiple myeloma by quantifying circulating clonal plasma cells

“…Despite the presence of high levels of cPCs in this study being associated with traditional adverse prognostic factors such as high risk cytogenetics, PCLI >2%, elevated LDH levels and BMPC ≥50%, it is an independent prognostic factor in the multivariable model outlined in Table S2. Pre‐clinical models have suggested the importance of interactions between cPCs in MM and the bone marrow microenvironment as a requirement for growth, proliferation and resistance mechanism to treatment . Thus, the presence of cPCs has suggested a more aggressive disease biology by their independence from their bone marrow microenvironment.…”

Genomic and transcriptomic profiles and in vitro resistance to mitoxantrone and idarubicin in pediatric acute leukemias

“…We assume that anthracycline resistance can be deepened through disorders in the integrin pathway. The role of integrin signaling in the lack of sensitivity to drugs has been already described in other types of cancer, such as myeloma cell lines , laryngeal carcinoma cells and breast cancer , as well as in AL . This is why we indicate the up‐regulation of ITGB2 as a potential marker in IDA resistance.…”

Multiple Myeloma: Available Therapies and Causes of Drug Resistance

“…Increase of cell adhesion molecules (VLA4) [159]. Corticosteroids (dexamethasone, prednisolone, methylprednisolone)…”

“…The CAMs located at the cell surface of MM cells are the lymphocyte function-associated antigen 1 (LFA1) and very late antigen 4 (VLA4), while the CAMs at the cell surface of BMSCs are the intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) [120,166]. In MM cell lines, the adhesion of myeloma cells, via VLA4, to the ECM component fibronectin prevented apoptosis and contributed to doxorubicin and melphalan resistance [159]. Concerning SDF-1/CXCL12, it is constitutively expressed and released by BMSCs and fibroblasts, while its receptor C-X-C chemokine receptor type 4 (CXCR4) is found in MM cells.…”