报告学者简介以及论文摘要
克劳丁·凯伊达：
法国国家科学研究中心研究主任，波兰克拉科雅盖隆大学教授以及分子肿瘤学和波兰华沙创新药物实验室主任。
主要发现：1986年——双凝集素糖复合物在肿瘤内皮细胞转移过程的识别；2002年——内皮细胞器官特异性演示；2006 年——理疗对在组织的作用示范；2006 年——三焦磷酸肌醇在血管生成中的作用；2013 年——三焦磷酸肌醇通过血管正常化在缓解肿瘤缺氧中所起作用的演示，对肿瘤演变的影响；影响辅助治疗；2014 年——通过内皮祖细胞血管生成正常化作用的演示和适应缺氧条件下治疗基因的表达；2016 年——三焦磷酸肌醇基因在肿瘤抑制基因PTEN上的活性。
Cancer hypoxia alleviation by ITPP-induced stable vessel normalization: an adjuvant tumor therapeutic strategy
Claudine Kieda
Laboratory of molecular oncology and Innovative therapies, WIM, Warsaw Poland National Centre for Scientific Research, Centre for Molecular Biophysics, Orleans France
Abstract:
In pO2-associated pathologies as cancer hypoxia turns on angiogenesis. Impaired O2-delivery contributes to tumor growth, metastasis and hypoxia-selection of aggressive cancer stem-like cells. Consequently, the anticancer strategies directed to pathological angiogenesis and its destruction are being revisited towards normalization. This challenge is reached by several pO2 control strategies which, are able to normalize tumor vessels thus, change the tumor microenvironment deeply enough to revert the immune tolerance into efficient immune response.
Clinical strategies take advantage of the pO2 increase that occurs in adapted antiangiogenic protocols to transiently regulate vessels structure and re-establish their function. Meanwhile, other cancer therapies can be beneficially applied. Success depends on the reliability of O2 imaging, measurement and the stabilization of the pO2 alleviation/vessel normalization. We have shown that such a strategy aiming to serve as adjuvant to chemo- and radiotherapy and ultimately overtake the pitfall of immune tolerance can be achieved by restoring an efficient antitumor response. Stabilization of vasculature normalization is the challenge that we could reach by several concordant approaches to increase stably the intra-tumor pO2:
-directly enhancing O2 delivery by red blood cells using an effector of hemoglobin: the myo inositol tris pyrophosphate (ITPP). We did demonstrate that it raises the oxygen tension inside the tumor and elevates the blood flow thus making functional the blood vessels.
-ITPP also controls PI3K/AKT/mTOR pathway as we could show that it stabilizes the activity of the tumor suppressor PTEN thus allows stable angiogenesis normalization.
The mechanism of the pO2 increase beneficial effect was confirmed by targeting the the tumor site by therapeutic gene expressed in a hypoxia-restricted manner: VEGF trap conditioned to hypoxia (soluble VEGF receptor-2) with precursor endothelial cells as gene carriers. These methods allowed the demonstration that hypoxia compensation helps radiotherapy and/or chemotherapy, moreover we show that by reverting pathologic angiogenesis, immune tolerance is converted into efficient immune response.
用三焦磷酸肌醇诱导稳定血管正常化缓解癌缺氧：辅助肿瘤治疗策略
克劳丁·凯伊达 波兰华沙维姆分子肿瘤学和创新疗法实验室 法国奥尔良国家科学研究中心、分子生物物理学研究中心
摘要：
在氧分压为癌相关疾病缺氧打开血管生成。氧释放受损是造成侵袭性肿瘤干细胞生长、转移和缺氧选择的原因。因此，直接针对病理性血管生成及其所造成的破坏的抗癌策略正在重新走向正常化。这种挑战被几个氧分压控制策略完成，就是能够使肿瘤血管正常化，极大改变肿瘤微环境，从而足以使免疫耐受转变成有效的免疫应答。
临床策略利用发生在血管生成的协议适应瞬时调节血管结构和重建他们的功能的氧分压增加的优势。同时，其他的癌症治疗也可以很好地应用。成功与否取决于O2成像，测量和氧分压稳定的可靠程度，我们已经证明，通过恢复有效的抗肿瘤反应，可以实现这样一种策略，即辅助化疗和放疗，最终克服免疫耐受的缺陷。我们可以通过一些一致的方法稳定增加肿瘤内氧分压，完成血管正常化的稳定性这一挑战：
— 利用血红蛋白效应器: 三焦磷酸肌醇（ITPP）, 红血球即可提高氧输送。我们确实证明它能提高肿瘤内部的氧张力，使血液流动，从而使血管功能正常。
— ITPP还控制PI3K/Akt/mTOR通路, 正如我们可以显示的，它稳定了肿瘤抑制基因PTEN的活性从而获得稳定的血管生成正常化。
氧分压增加的有益作用机制是通过在缺氧的限制方式靶向肿瘤部位的治疗基因表达中得到证实：，血管内皮生长因子抑制剂（VEGF Trap）被限制在作为基因载体的内皮细胞前体缺氧（可溶性VEGF受体）中。这些方法证明缺氧代偿有助于放疗和/或化疗，而且我们表明，通过恢复病理性血管生成，免疫耐受转化为有效的免疫应答。
