RESUMO
Thrombocytosis is present in more than 30% of patients with solid malignancies and correlates with worsened patient survival. Tumor cell interaction with various cellular components of the tumor microenvironment including platelets is crucial for tumor growth and metastasis. Although it is known that platelets can infiltrate into tumor tissue, secrete pro-angiogenic and pro-tumorigenic factors and thereby increase tumor growth, the precise molecular interactions between platelets and metastatic cancer cells are not well understood. Here we demonstrate that platelets induce resistance to anoikis in vitro and are critical for metastasis in vivo. We further show that platelets activate RhoA-MYPT1-PP1-mediated YAP1 dephosphorylation and promote its nuclear translocation which induces a pro-survival gene expression signature and inhibits apoptosis. Reduction of YAP1 in cancer cells in vivo protects against thrombocytosis-induced increase in metastasis. Collectively, our results indicate that cancer cells depend on platelets to avoid anoikis and succeed in the metastatic process.Platelets have been associated with increased tumor growth and metastasis but the mechanistic details of this interaction are still unclear. Here the authors show that platelets improve anoikis resistance of cancer cells and increase metastasis by activating Yap through a RhoA/MYPT-PP1 pathway.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Anoikis , Plaquetas/metabolismo , Neoplasias Ovarianas/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Plaquetas/citologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Nus , Metástase Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosfoproteínas/genética , Interferência de RNA , Fatores de Transcrição , Transplante Heterólogo , Proteínas de Sinalização YAPRESUMO
Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quinase 1 de Adesão Focal/metabolismo , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Difosfato de Adenosina/metabolismo , Animais , Anticorpos Antineoplásicos/farmacologia , Bevacizumab/farmacologia , Plaquetas/patologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Linhagem Celular Tumoral , Feminino , Quinase 1 de Adesão Focal/antagonistas & inibidores , Quinase 1 de Adesão Focal/genética , Humanos , Indazóis , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neovascularização Patológica/enzimologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: XPO1 inhibitors have shown promise for cancer treatment, and yet the underlying mechanisms for the antitumor effects are not well understood. In this study, we explored the usefulness of selective inhibitors of nuclear export (SINE) compounds that are specific inhibitors of XPO1. EXPERIMENTAL DESIGN: We used proteomic analysis in XPO1 inhibitor-treated ovarian cancer cell lines and examined antitumor effects in ovarian and breast cancer mouse models. We also studied the effects of XPO1 inhibitor in combination with chemotherapeutic agents. RESULTS: XPO1 inhibitor treatment substantially increased the percentage of apoptotic cells (60%) after 72 hours of incubation. XPO1 inhibitor promoted the accumulation of eIF5A in mitochondria, leading to cancer cell death. Topotecan showed the greatest synergistic effect with XPO1 inhibitor. XPO1 inhibitors prevented the translocation of IGF2BP1 from the nucleus to the cytoplasm, thereby permitting the localization of eIF5A in the mitochondria. This process was p53, RB, and FOXO independent. Significant antitumor effects were observed with XPO1 inhibitor monotherapy in orthotopic ovarian (P < 0.001) and breast (P < 0.001) cancer mouse models, with a further decrease in tumor burden observed in combination with topotecan or paclitaxel (P < 0.05). This mitochondrial accumulation of eIF5A was highly dependent on the cytoplasmic IGF2BP1 levels. CONCLUSIONS: We have unveiled a new understanding of the role of eIF5A and IGF2BP1 in XPO1 inhibitor-mediated cell death and support their clinical development for the treatment of ovarian and other cancers. Our data also ascertain the combinations of XPO1 inhibitors with specific chemotherapy drugs for therapeutic trials.