Cancer Cell Circuitry Laboratory, Institute of Biomedicine, Biochemistry and Developmental Biology & Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
Adv Cancer Res. 2011;111:97-161. doi: 10.1016/B978-0-12-385524-4.00003-9.
Epithelial architecture is formed in tissues and organs when groups of epithelial cells are organized into polarized structures. The epithelial function and integrity as well as signaling across the epithelial layer is orchestrated by apical junctional complexes (AJCs), which are landmarks for PAR/CRUMBS and lateral SCRIB polarity modules and by dynamic interactions of the cells with underlying basement membrane (BM). These highly organized epithelial architectures are demolished in cancer. In all advanced epithelial cancers, malignant cells have lost polarity and connections to the basement membrane and they have become proliferative, motile, and invasive. Clearly, loss of epithelial integrity associates with tumor progression but does it contribute to tumor development? Evidence from studies in Drosophila and recently also in vertebrate models have suggested that even the oncogene-driven enforced cell proliferation can be conditional, dependant on the influence of cell-cell or cell-microenvironment contacts. Therefore, loss of epithelial integrity may not only be an obligate consequence of unscheduled proliferation of malignant cells but instead, malignant epithelial cells may need to acquire capacity to break free from the constraints of integrity to freely and autonomously proliferate. We discuss how epithelial polarity complexes form and regulate epithelial integrity, highlighting the roles of enzymes Rho GTPases, aPKCs, PI3K, and type II transmembrane serine proteases (TTSPs). We also discuss relevance of these pathways to cancer in light of genetic alterations found in human cancers and review molecular pathways and potential pharmacological strategies to revert or selectively eradicate disorganized tumor epithelium.
上皮组织的形态结构是由上皮细胞组成的极性结构形成的。上皮细胞的功能和完整性以及上皮层之间的信号传递是由顶端连接复合体（AJC）协调的，AJC 是 PAR/CRUMBS 和侧向 SCRIB 极性模块的地标，也是细胞与基底膜（BM）动态相互作用的地标。这些高度组织化的上皮结构在癌症中被破坏。在所有高级上皮癌中，恶性细胞失去了极性和与基底膜的连接，并且变得增殖、运动和侵袭。显然，上皮完整性的丧失与肿瘤进展相关，但它是否有助于肿瘤的发展？来自果蝇和最近脊椎动物模型的研究证据表明，即使是受致癌基因驱动的强制性细胞增殖也可能是有条件的，取决于细胞-细胞或细胞-微环境接触的影响。因此，上皮完整性的丧失可能不仅是恶性细胞无计划增殖的必然结果，相反，恶性上皮细胞可能需要获得摆脱完整性限制的能力，以便自由和自主地增殖。我们讨论了上皮极性复合物的形成和调节上皮完整性的方式，强调了 Rho GTPases、aPKCs、PI3K 和 II 型跨膜丝氨酸蛋白酶（TTSP）等酶的作用。我们还根据在人类癌症中发现的遗传改变，讨论了这些途径与癌症的相关性，并回顾了逆转或选择性根除组织紊乱的肿瘤上皮的分子途径和潜在的药理学策略。
