Background/Objectives: The progression of colorectal cancer through clinically and histopathologically well-defined stages is driven by specific mutations that activate oncogenes or inactivate tumor-suppressor genes. In addition, pre-cancerous/cancer cells respond to cues from the tissue microenvironment that support tumorigenesis and progression, many of which are transmitted through integrin receptors for the extracellular matrix. Integrin α3β1 has pro-tumorigenic/pro-metastatic roles in many cancers, but it also has suppressive roles in some cancers or at specific stages of progression, indicating that its potential value as a therapeutic target cannot be extrapolated across cancer types or stages. In this study, we investigated roles for α3β1 in colorectal cancer using cellular and genetic models that represent different stages. Methods: We generated mice with colon-specific α3 knockout in a tamoxifen-inducible model ofKRAS-mutated colorectal cancer to assess the effects of α3β1 ablation on early dysplasia. We also used siRNA to suppress α3β1 in human colorectal cancer cells, then assessed effects on motility and invasion in vitro. Results: Genetic deletion of α3β1 in the colon did not alter dysplasia in mice predisposed toKRAS-mutated colorectal cancer, and it was accompanied by an increase in the colocalization of α6 integrin with laminin-332 (a matrix ligand for both integrins), suggesting functional compensation. However, suppression of α3β1 caused an approximately 40% to 60% reduction in the motility/invasion of human colorectal cancer cells. Conclusions: Our findings that α3β1 is not required for pre-cancerous dysplasia but promotes colorectal cancer cell motility/invasion indicate an important role for pro-migratory functions of this integrin at later stages of progression when cells invade from the primary tumor, suggesting that strategies to target α3β1 in colorectal cancer should be aimed at distinct stages of disease progression.
背景/目的：结直肠癌通过临床和组织病理学上明确定义的阶段进展，是由激活癌基因或失活抑癌基因的特定突变驱动的。此外，癌前/癌细胞会对来自组织微环境的信号作出反应，这些信号支持肿瘤发生和进展，其中许多信号是通过细胞外基质的整合素受体传递的。整合素α3β1在许多癌症中具有促肿瘤发生/促转移作用，但在某些癌症或特定进展阶段也具有抑制作用，这表明其作为治疗靶点的潜在价值不能在不同癌症类型或阶段中一概而论。在本研究中，我们使用代表不同阶段的细胞和遗传模型，研究了α3β1在结直肠癌中的作用。方法：我们在他莫昔芬诱导的KRAS突变结直肠癌模型中，构建了结肠特异性α3基因敲除小鼠，以评估α3β1缺失对早期发育不良的影响。我们还使用siRNA抑制人结直肠癌细胞中的α3β1，然后在体外评估其对细胞运动和侵袭的影响。结果：在易患KRAS突变结直肠癌的小鼠中，结肠α3β1的基因缺失并未改变发育不良，并且伴随着α6整合素与层粘连蛋白-332（两种整合素的基质配体）共定位的增加，这表明存在功能补偿。然而，抑制α3β1导致人结直肠癌细胞的运动/侵袭能力降低约40%至60%。结论：我们的研究结果表明，α3β1在癌前发育不良中并非必需，但能促进结直肠癌细胞的运动/侵袭，这表明该整合素的促迁移功能在细胞从原发肿瘤侵袭的后期进展阶段具有重要作用，提示针对结直肠癌中α3β1的治疗策略应针对疾病进展的不同阶段。
肿瘤(癌症)患者之家