RESUMO
VEGF stimulates endothelial cells as a key molecule in angiogenesis. VEGF also works as a multifunction molecule, which targets a variety of cell members in the tumor microenvironment. We aimed to reveal VEGF-related molecular mechanisms on breast cancer cells. VEGF-knocked-out MDA-MB-231 cells (231 VEGFKOex3 ) showed rounded morphology and shorter perimeter (1.6-fold, p < 0.0001). The 231 VEGFKOex3 cells also showed impaired cell migration (2.6-fold, p = 0.002). Bevacizumab treatment did not induce any change in morphology and mobility. Soluble neuropilin-1 overexpressing MDA-MB-231 cells (231 sNRP1 ) exhibited rounded morphology and shorter perimeter (1.3-fold, p < 0.0001). The 231 sNRP1 cells also showed impaired cell migration (1.7-fold, p = 0.003). These changes were similar to that of 231 VEGFKOex3 cells. As MDA-MB-231 cells express almost no VEGFR, these results indicate that the interaction between NRP1 and long isoform of VEGF containing a NRP-binding domain regulates the morphology and migration ability of MDA-MB-231 cells. Genome-wide gene expression profiling identified ARHGAP17 as one of the target genes in the downstream of the VEGF/NRP1 signal. We also show that VEGF/NRP1 signal controls filopodia formation of the cells by modulating Cdc42 activity via ARHGAP17. Among 1,980 breast cancer cases from a public database, the ratio of VEGF and SEMA3A in primary tumors (n = 450) of hormone-receptor-negative breast cancer is associated with ARHGAP17 expression inversely, and with disease free survival. Altogether, the bevacizumab-independent VEGF/NRP1/ARHGAP17/Cdc42 regulatory network plays important roles in malignant behavior of breast cancer.
Assuntos
Neoplasias da Mama/metabolismo , Movimento Celular/fisiologia , Proteínas Ativadoras de GTPase/metabolismo , Neuropilina-1/metabolismo , Isoformas de Proteínas/metabolismo , Pseudópodes/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Ligação Proteica/fisiologia , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais/fisiologiaRESUMO
A 73-year-old woman, who was diagnosed with right triple negative breast cancer (cT1cN1M0, stage I ) and underwent right modified radical mastectomy with axillary lymph node dissection, showed recurrent disease in the right parasternal lymph node 4 years after the operation. Computed tomography (CT) revealed rapid growth of the tumor along with pain, accompanied by the destruction of the sternal bone. Five cycles of bevacizumab plus paclitaxel (BEV+wPTX) treatment (10 mg/kg of bevacizumab on days 1 and 15 plus 90 mg/m² of paclitaxel on days 1, 8, and 15 every 4 weeks)achieved remarkable tumor regression. Parasternal irradiation (30 Gy/15 Fr) followed by oral capecitabine treatment (600 mg b. i. d; 3 week administration followed by a week of rest) as maintenance therapy showed complete tumor regression and helped to achieve good quality of life (QOL) without any unfavorable symptoms at the 2-year follow-up, although the estimated progression free survival of this treatment is about 6 months. As BEV+wPTX had a high response rate for recurrent breast cancer, its combination with sequential radiotherapy could provide a favorable local control rate and good QOL for patients with rapidly growing, solitary, recurrent breast cancers.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Parede Torácica/patologia , Neoplasias de Mama Triplo Negativas/terapia , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Progressão da Doença , Feminino , Humanos , Mastectomia Radical Modificada , Paclitaxel/administração & dosagem , Recidiva , Indução de Remissão , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Metaplastic breast carcinoma in neurofibromatosis type 1 is extremely rare. There are few reports about dynamic contrast-enhanced MRI findings and sequential CT findings of metaplastic breast carcinoma in neurofibromatosis type 1. Herein, we report imaging findings, including dynamic contrast-enhanced MRI and sequential CT, of metaplastic breast carcinoma in an 82-year-old woman with neurofibromatosis type 1. Short tau inversion recovery image revealed an oval mass with a circumscribed margin that exhibited moderate intensity with partially hyperintense area inside, and T1-weighted imaging revealed a spotty hyperintense area. The solid component of the mass showed heterogeneous enhancement and the time-intensity curve had a fast/washout pattern with restricted diffusion. In addition, multiple neurofibromas were observed. Sequential CT revealed that the diameter of the mass doubled in 3 months without apparent lymph node metastasis. Because detection of metaplastic breast carcinoma in neurofibromatosis type 1 tends to be delayed due to multiple neurofibromas, characteristic MRI findings suggestive of metaplastic breast carcinoma and sequential CT findings are important for early treatment of metaplastic breast carcinoma in patients with neurofibromatosis type 1.