Ovarian tumor attachment, invasion, and vascularization reflect unique microenvironments in the peritoneum: insights from xenograft and mathematical models.
Ovarian tumor attachment, invasion, and vascularization reflect unique microenvironments in the peritoneum: insights from xenograft and mathematical models.
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DOI：
10.3389/fonc.2013.00097
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发表时间：
2013
影响因子：
4.7
通讯作者：
Wilson BS
中科院分区：
文献类型：
--
作者：
Steinkamp MP;Winner KK;Davies S;Muller C;Zhang Y;Hoffman RM;Shirinifard A;Moses M;Jiang Y;Wilson BS
卵巢癌复发的典型特征往往是癌细胞转移播散至整个腹腔，肿瘤附着于多个器官。在本研究中，通过腹腔注射荧光标记的SKOV3.ip1卵巢癌细胞构建异种移植模型，对卵巢癌细胞与腹膜肿瘤微环境之间的相互作用进行了评估。对注入腹腔的绿色荧光蛋白（GFP）和红色荧光蛋白（RFP）混合细胞群体进行活体显微镜观察，结果显示癌细胞以混合球体的形式聚集并附着，这突出了同型黏附在肿瘤形成过程中的重要性。电子显微镜则提供了局部附着位点的高分辨率结构信息。利用小鼠模型的实验测量数据，构建了三维细胞Potts卵巢肿瘤模型（OvTM），用于研究卵巢癌细胞的附着、趋化性、生长及血管生成情况。OvTM模拟有助于深入了解癌细胞间黏附、氧气供应以及局部结构对肿瘤生长和形态的相对影响。值得注意的是，肠系膜、大网膜或脾脏上的肿瘤很容易侵入 “开放” 结构，而附着在肠道上的肿瘤则会遇到限制其侵入的屏障，反而会迅速向腹腔空间扩张。模拟结果表明，在无缺氧条件下，血管生成因子的持续释放会引发SKOV3.ip1肿瘤的快速新生血管形成。本研究强调了细胞黏附和肿瘤微环境在腹腔内不同器官上继发性卵巢肿瘤播散过程中的重要性。OvTM模拟结果表明，肿瘤的侵入受不同部位间皮衬里潜在特征的强烈影响，同时也受趋化因子局部产生的影响。体内小鼠模型与计算机模拟相结合，为评估卵巢癌复发的靶向治疗提供了一个独特的平台。
Ovarian cancer relapse is often characterized by metastatic spread throughout the peritoneal cavity with tumors attached to multiple organs. In this study, interaction of ovarian cancer cells with the peritoneal tumor microenvironment was evaluated in a xenograft model based on intraperitoneal injection of fluorescent SKOV3.ip1 ovarian cancer cells. Intra-vital microscopy of mixed GFP-red fluorescent protein (RFP) cell populations injected into the peritoneum demonstrated that cancer cells aggregate and attach as mixed spheroids, emphasizing the importance of homotypic adhesion in tumor formation. Electron microscopy provided high resolution structural information about local attachment sites. Experimental measurements from the mouse model were used to build a three-dimensional cellular Potts ovarian tumor model (OvTM) that examines ovarian cancer cell attachment, chemotaxis, growth, and vascularization. OvTM simulations provide insight into the relative influence of cancer cell–cell adhesion, oxygen availability, and local architecture on tumor growth and morphology. Notably, tumors on the mesentery, omentum, or spleen readily invade the “open” architecture, while tumors attached to the gut encounter barriers that restrict invasion and instead rapidly expand into the peritoneal space. Simulations suggest that rapid neovascularization of SKOV3.ip1 tumors is triggered by constitutive release of angiogenic factors in the absence of hypoxia. This research highlights the importance of cellular adhesion and tumor microenvironment in the seeding of secondary ovarian tumors on diverse organs within the peritoneal cavity. Results of the OvTM simulations indicate that invasion is strongly influenced by features underlying the mesothelial lining at different sites, but is also affected by local production of chemotactic factors. The integrated in vivo mouse model and computer simulations provide a unique platform for evaluating targeted therapies for ovarian cancer relapse.