Institute of Physiological Chemistry and Pathobiochemistry, Münster University Hospital, 48149 Münster, Germany.
Int J Mol Sci. 2017 Nov 7;18(11):2355. doi: 10.3390/ijms18112355.
After oncogenic transformation, tumor cells rewire their metabolism to obtain sufficient energy and biochemical building blocks for cell proliferation, even under hypoxic conditions. Glucose and glutamine become their major limiting nutritional demands. Instead of being autonomous, tumor cells change their immediate environment not only by their metabolites but also by mediators, such as juxtacrine cell contacts, chemokines and other cytokines. Thus, the tumor cells shape their microenvironment as well as induce resident cells, such as fibroblasts and endothelial cells (ECs), to support them. Fibroblasts differentiate into cancer-associated fibroblasts (CAFs), which produce a qualitatively and quantitatively different extracellular matrix (ECM). By their contractile power, they exert tensile forces onto this ECM, leading to increased intratumoral pressure. Moreover, along with enhanced cross-linkage of the ECM components, CAFs thus stiffen the ECM. Attracted by tumor cell- and CAF-secreted vascular endothelial growth factor (VEGF), ECs sprout from pre-existing blood vessels during tumor-induced angiogenesis. Tumor vessels are distinct from EC-lined vessels, because tumor cells integrate into the endothelium or even mimic and replace it in vasculogenic mimicry (VM) vessels. Not only the VM vessels but also the characteristically malformed EC-lined tumor vessels are typical for tumor tissue and may represent promising targets in cancer therapy.
致癌转化后，肿瘤细胞重新调整其代谢以获取足够的能量和生化构建块来支持细胞增殖，即使在缺氧条件下也是如此。葡萄糖和谷氨酰胺成为它们主要的限制营养需求。肿瘤细胞不仅通过其代谢物，还通过旁分泌细胞接触、趋化因子和其他细胞因子等介质来改变其周围环境。因此，肿瘤细胞不仅塑造了它们的微环境，还诱导了驻留细胞（如成纤维细胞和内皮细胞[ECs]）来支持它们。成纤维细胞分化为癌相关成纤维细胞（CAFs），产生质和量均不同的细胞外基质（ECM）。通过它们的收缩力，它们对 ECM 施加张力，导致肿瘤内压力增加。此外，随着 ECM 成分交联的增强，CAFs 使 ECM 变硬。EC 受到肿瘤细胞和成纤维细胞分泌的血管内皮生长因子（VEGF）的吸引，在肿瘤诱导的血管生成过程中从预先存在的血管中发芽。肿瘤血管与 EC 衬里的血管不同，因为肿瘤细胞整合到内皮细胞中，甚至在血管生成拟态（VM）血管中模拟并替代它。不仅 VM 血管，而且特征性畸形的 EC 衬里肿瘤血管也是肿瘤组织的典型特征，可能成为癌症治疗的有前途的靶点。
