Cell-cell and cell-matrix adhesion in survival and metastasis: Stat3 versus Akt
Cell-cell and cell-matrix adhesion in survival and metastasis: Stat3 versus Akt
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DOI：
10.1515/bmc-2015-0022
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发表时间：
2015-12-01
影响因子：
--
通讯作者：
Raptis, Leda
中科院分区：
文献类型：
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作者：
Niit, Maximilian;Hoskin, Victoria;Raptis, Leda
细胞-细胞和细胞-基质粘附对于上皮细胞分化和功能都是重要的。经典钙粘蛋白介导细胞与细胞的相互作用，是信号转导和转录激活因子（Stat 3）的有效激活剂，从而提供生存信号。虽然上皮（E）-钙粘蛋白是细胞在分化的上皮组织内保持紧密结合所必需的，但钙粘蛋白-11促进侵袭和转移，优先向骨侵袭和转移。细胞与细胞外基质的粘附是通过与粘着斑激酶（FAK）/Src复合物结合的整联蛋白受体介导的，从而激活下游效应物如Ras/Erk 1/2和PI 3 k/Akt，但不激活Stat 3。因此，在高密度的培养细胞或上皮组织中，互补的钙粘蛋白/Stat 3和整联蛋白/FAK途径的协同激活可以极大地增强肿瘤细胞的存活和生长。另一方面，在肿瘤转化细胞中，多种癌基因包括激活的Src或受体酪氨酸激酶，激活两种途径。尽管如此，大多数针对这些信号通路的单药疗法在临床上还是令人失望的。Src/FAK和Stat 3通路与抑制性药物的组合靶向预期在抑制肿瘤细胞存活方面具有更大的功效，并且增强对用于治疗转移性疾病的常规细胞毒性药物的敏感性。
Both cell-cell and cell-matrix adhesion are important for epithelial cell differentiation and function. Classical cadherins mediate cell to cell interactions and are potent activators of the signal transducer and activator of transcription (Stat3), thereby offering survival signaling. While the epithelial (E)-cadherin is required for cells to remain tightly associated within differentiated epithelial tissues, cadherin-11 promotes invasion and metastasis, preferentially to the bone. Cell adhesion to the extracellular matrix is mediated through the integrin receptors that bind to the focal adhesion kinase (FAK)/Src complex, thus activating downstream effectors such as Ras/Erk1/2 and PI3k/Akt, but not Stat3. Therefore, at high densities of cultured cells or in epithelial tissues, co-ordinate activation of the complementary cadherin/Stat3 and integrin/FAK pathways can greatly enhance survival and growth of tumor cells. In neoplastically transformed cells on the other hand, a variety of oncogenes including activated Src or receptor tyrosine kinases, activate both pathways. Still, most single-agent therapies directed against these signaling pathways have proven disappointing in the clinic. Combined targeting of the Src/FAK and Stat3 pathways with inhibitory drugs would be expected to have greater efficacy in inhibiting tumor cell survival, and enhancing sensitivity to conventional cytotoxic drugs for treatment of metastatic disease.