Mammadova-Bach Elmina, Rupp Tristan, Spenlé Caroline, Jivkov Ivo, Shankaranarayanan Pattabhiraman, Klein Annick, Pisarsky Laura, Méchine-Neuville Agnès, Cremel Gérard, Kedinger Michèle, De Wever Olivier, Ambartsumian Noona, Robine Sylvie, Pencreach Erwan, Guenot Dominique, Simon-Assmann Patricia, Goetz Jacky G, Orend Gertraud, Lefebvre Olivier
Inserm U1109, MN3T, Strasbourg, F-67200, France.
Université de Strasbourg, Strasbourg, F-67000, France.
Biol Cell. 2018 Jun 15. doi: 10.1111/boc.201800007.
Tumor stroma remodeling is a key feature of malignant tumors and can promote cancer progression. Laminins are major constituents of basement membranes that physically separate the epithelium from the underlying stroma.
By employing mouse models expressing high and low levels of the laminin α1 chain (LMα1), we highlighted its implication in a tumor-stroma crosstalk, thus leading to increased colon tumor incidence, angiogenesis and tumor growth. The underlying mechanism involves attraction of carcinoma-associated fibroblasts by LMα1, VEGFA expression triggered by the complex integrin α2β1-CXCR4 and binding of VEGFA to LM-111, which in turn promotes angiogenesis, tumor cell survival and proliferation. A gene signature comprising LAMA1, ITGB1, ITGA2, CXCR4 and VEGFA has negative predictive value in colon cancer.
Together, we have identified VEGFA, CXCR4 and α2β1 integrin downstream of LMα1 in colon cancer as of bad prognostic value for patient survival.
This information opens novel opportunities for diagnosis and treatment of colon cancer.
肿瘤基质重塑是恶性肿瘤的关键特征，可促进癌症进展。层粘连蛋白是基底膜的主要成分，它将上皮细胞与下方的基质物理分隔开。
通过使用表达高水平和低水平层粘连蛋白α1链（LMα1）的小鼠模型，我们强调了其在肿瘤-基质相互作用中的作用，从而导致结肠癌发病率、血管生成和肿瘤生长增加。潜在机制包括LMα1对癌相关成纤维细胞的吸引、由整合素α2β1-CXCR4复合物触发的VEGFA表达以及VEGFA与LM-111的结合，进而促进血管生成、肿瘤细胞存活和增殖。由LAMA1、ITGB1、ITGA2、CXCR4和VEGFA组成的基因特征在结肠癌中具有阴性预测价值。
我们共同确定，结肠癌中LMα1下游的VEGFA、CXCR4和α2β1整合素对患者生存具有不良预后价值。
这一信息为结肠癌的诊断和治疗开辟了新的机会。
