Abstract
Integrin β3 (ITGB3) is probably related to skeletal metastasis, which is the most frequent complication in breast cancer progression. We aimed to define its role and suitability as target for anti-metastatic therapy. We generated two MDA-MB-231 cell clones with conditional miRNA-mediated ITGB3 knockdown for analyzing the resulting effects in vitro regarding mRNA expression, proliferation and migration, as well the impact on skeletal metastasis in a nude rat model. Furthermore, ITGB3 levels were analyzed in exosomes from plasma of rats with skeletal metastases, and from MDA-MB-231 cells incubated with these vesicles, as well as from exosomes secreted by cells with conditional ITGB3 knockdown. This inhibition of ITGB3 expression decreased cellular proliferation and more distinctly inhibited cellular migration. Reduction and even complete remissions of respective soft tissue and osteolytic lesions were detected after ITGB3 knockdown in vivo. Furthermore, ITGB3 levels were increased in exosomes isolated from plasma of rats harboring MDA-MB-231 lesions as well as in respective cells incubated with these vesicles in vitro. ITGB3 was distinctly decreased in exosomes from cells with ITGB3 knockdown. The observed in vitro and in vivo anti-ITGB3 effects can be explained by downregulation of specific genes, which have roles in angiogenesis (NPTN, RRM2), tumor growth (NPTN), energy metabolism (ISCA1), cytokinesis (SEPT11), migration (RRM2, STX6), cell proliferation, invasiveness, senescence, tumorigenesis (RRM2) and vesicle trafficking (SEPT11, STX6). ITGB3 has a role in breast cancer skeletal metastasis via gene expression modulation, as mirrored for ITGB3 in exosomes, thus it could serve as target for anti-metastatic therapy.
Highlights
Integrins are a family of transmembrane proteins, which integrate the extracellular matrix processes and the intracellular compartment activities (Raab-Westphal et al 2017)
According to several published reports, integrin β3 is an interesting option, as it is expressed by breast cancer cells (Das et al 2018) and its heterodimer αvβ3 is related to high rates of bone metastasis, tumor-associated osteolysis
It is more and more clear that these exosomes could have a functional role in determining organ sites of potential metastasis, as they aid in preparing the microenvironment of the pre-metastatic niche, which supports cancer cell survival (Hoshino et al 2015)
Summary
Integrins are a family of transmembrane proteins, which integrate the extracellular matrix processes and the intracellular compartment activities (Raab-Westphal et al 2017). It is known that integrin αvβ has low or undetectable levels of expression in most adult epithelia and resting endothelial cells in non-diseased tissues, whereas in breast and prostate cancers, and in activated tumor endothelial cells it is highly expressed (Desgrosellier and Cheresh 2010; Bauerle et al 2011). Bone metastasis is the most frequent complication in breast cancer, which is occurring in 70% of the affected patients (Roodman 2004). This complication has devastating consequences and increases the risk of skeletal related events like severe pain, pathologic fractures, life-threatening hypercalcemia, alteration of hematopoiesis by bone marrow infiltration, spinal cord or nerve rootscompression, which may have decisive impact on the quality of life, morbidity and mortality of cancer patients (Roodman 2004; Uccello et al 2011). The lack of novel treatment led to the urgent necessity of deciphering the mechanism of the metastatic process and of finding a valuable target for anti-metastatic therapy
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