VEGF-C-dependent host-tumor interactions that promote metastasis in response to chemotherapy

化疗和靶向抗癌药物强烈地限制或逆转了肿瘤的生长。然而，宿主组织对治疗的反应可以通过促进肿瘤的再生长和/或转移来抵消这些治疗方法的抗肿瘤活性，从而限制其疗效。我们以前已经发现，局部和全身的血管内皮生长因子-C的表达显著增加，这是紫杉醇(PTX)化疗的一种宿主反应。这会导致肿瘤新生淋巴管生成增加，从而支持转移。我们发现，VEGF-C的主要受体VEGFR-3表达于化疗激活的巨噬细胞表面。它的表达主要通过促进组织蛋白等蛋白酶的分泌来促进淋巴管的生成，从而导致肝素酶活性增加和血管内皮生长因子-C表达增加。我们还证明，系统的血管内皮生长因子-C的上调诱导CD11b/Ly6G中性粒细胞重新聚集到肺部，这足以诱导转移的形成。值得注意的是，VEGFR3/VEGF-C轴通过招募免疫细胞促进肺转移。然而，该轴下游的细胞和分子机制尚不清楚。这项建议的主要目的是剖析全身血管内皮生长因子-C增加导致化疗耐药和转移的细胞和分子途径。具体地说，我们的目标是(I)确定肺巨噬细胞增加全身血管内皮生长因子-C的反应及其与中性粒细胞的串扰；(Ii)评估PTX教育的髓系细胞在肺内ECM重塑和肿瘤细胞种植中的贡献，以及ECM重塑酶在这一过程中的作用；(Iii)研究PTX诱导转移的机制是否与其他化疗药物相同。这项研究将对化疗后血管内皮生长因子C-VEGFR3信号促进促进转移的器官微环境发展的基本机制提供新的见解。这项研究的长期目标是开发新的方法来阻断促肿瘤和促转移的宿主对化疗的反应，从而提高当前治疗方式的有效性。

Chemotherapy and targeted anti-cancer drugs strongly restrict or reverse tumor growth. However, the response of host tissue to therapy can counteract the anti-tumor activity of these therapies by promoting tumor re-growth and/or metastases, thus limiting their efficacy. We have previously identified greatly increased VEGF-C expression, both locally and systemically, as one such host response to paclitaxel (PTX) chemotherapy. This leads to increased tumor neo-lymphangiogenesis that supports metastasis. We found that VEGFR-3, the main receptor for VEGF-C, is expressed on the surface of chemotherapy-activated macrophages. Its expression contributes to lymphangiogenesis largely by promoting the secretion of proteases such as cathepsins, which leads to increased heparanase activity and increased VEGF-C expression. We also demonstrated that upregulation of systemic VEGF-C induces the recruitment of CD11b+/Ly6G+ neutrophils to the lungs, which suffices to induce metastasis formation. The observation that the VEGFR3/VEGF-C axis promotes metastasis to the lung by recruiting immune cells is remarkable. However, the cellular and molecular mechanisms downstream of this axis are unknown. The broad aim of this proposal is to dissect the cellular and molecular pathways through which increased systemic VEGF-C induces chemoresistance and metastasis. Specifically, we aim to (i) determine the response of pulmonary macrophages increased systemic VEGF-C and their crosstalk with neutrophils; (ii) evaluate the contribution of PTX-educated myeloid cells to ECM remodeling and tumor cell seeding in the lung, and the role of ECM remodeling enzymes in this process; (iii) examine whether the mechanisms of PTX-induced metastasis are shared with other chemotherapies. This study will provide new insights into the fundamental mechanisms through which VEGF-C-VEGFR3 signaling fosters the development of metastasis-promoting organ microenvironments following exposure to chemotherapy. The long-term goal of this study is to develop novel ways of blocking pro-tumorigenic and pro-metastatic host responses to chemotherapy, thereby increasing the efficacy of current treatment modalities.