In Vivo “MRI Phenotyping” Reveals Changes in Extracellular Matrix Transport and Vascularization That Mediate VEGF-Driven Increase in Breast Cancer Metastasis

PURPOSE: To gain new insights into the relationship between angiogenic factors in breast cancer and their effect on extracellular matrix (ECM) remodeling and metastasis, we characterized and validated the “metastatic signature” of human breast cancer cell lines engineered to overexpress VEGF in terms of in vivo MRI-derived angiogenesis and ECM transport parameters. METHODOLOGY: MRI was used to evaluate the effects of overexpressing VEGF-A (VEGF(165)) on tumor angiogenesis and ECM remodeling in vivo, for two differentially metastatic human breast cancer cell lines: MCF-7 and MDA-MB-231. PRINCIPAL FINDINGS: Overexpression of VEGF elevated vascular volume in both MCF-7-VEGF and MDA-MB-231-VEGF tumors relative to their wild-type counterparts, but vascular permeability was elevated only in MCF-7-VEGF tumors. A significant increase in the volume of extravascular fluid drained as well as the number of ECM drainage voxels was detected in MCF-7-VEGF tumors relative to MCF-7 tumors, but not in MDA-MB-231-VEGF versus MDA-MB-231 tumors. The angiogenic effects of VEGF overexpression in both MCF-7-VEGF and MDA-MB-231-VEGF tumors were validated histologically. MCF-7-VEGF tumors exhibited enhanced invasion and a greater fraction of cancer positive lungs and lymph nodes relative to MCF-7 tumors. CONCLUSIONS AND SIGNIFICANCE: In vivo MRI and histological data demonstrate that VEGF overexpression results in the progression of noninvasive MCF-7 and invasive MDA-MB-321 tumors to a more angiogenic phenotype. However, VEGF overexpression significantly altered ECM integrity only in MCF-7 tumors, causing them to progress to an invasive and metastatic phenotype. This study for the first time demonstrates the concurrent effects of VEGF overexpression and ECM remodeling on metastasis in vivo. Collectively, these findings demonstrate that in vivo MRI can non-invasively monitor changes in the tumor microenvironment that can potentially predict a cancer’s ability to metastasize.