Qureshi Asif M, Hannigan Adele, Campbell Donald, Nixon Colin, Wilson Joanna B
College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Genes Cancer. 2011 Jan;2(1):74-87. doi: 10.1177/1947601911402681.
An important role for B cells and immunoglobulin deposition in the inflammatory tumor cell environment has been recognized in several cancers, and this is recapitulated in our murine model of inflammation-associated carcinogenesis: transgenic mice expressing the Epstein-Barr virus oncogene LMP1 in epithelia. Similarly in several autoimmune disorders, immunoglobulin deposition represents a key underlying event in the disease process. However, the autoantigens in most cases are not known. In other studies, overexpression of the enzymatically inactive mammalian chitinase-like proteins (CLPs) has been observed in a number of autoimmune disorders and numerous cancers, with expression correlated with poor prognosis, although the function of these proteins is largely unknown. We have now linked these observations demonstrating that overexpression of the CLPs renders them the targets for autoantigenicity during carcinogenic progression. We show that the CLPs, Chi3L1, Chi3L3 /YM1, and Chi3L4/YM2, are abundantly overexpressed in the transgenic epidermis at an early, preneoplastic stage and secreted into the serum. Immunoglobulin G reactive to the CLPs is detected in the serum and deposited in the hyperplastic tissue, which goes on to become inflamed and progressively displastic. The CLPs are also upregulated in chemical carcinogen-promoted lesions in both transgenic and wild-type mice. Expression of the related, active chitinases, Chit1 and AMCase, increases following infiltration of inflammatory cells. In this model, the 3 CLPs are autoantigens for the tissue-deposited immunoglobulin, which we propose plays a causative role in promoting the inflammation-associated carcinogenesis. This may reflect their normal, benign function to promote tissue remodeling and to amplify immune responses. Their induction during carcinogenesis and consequent autoantigenicity provides a missing link between the oncogenic event and subsequent inflammation. This study identifies the CLPs as important and novel therapeutic targets to limit inflammation in cancer and potentially also autoimmune disorders.
B细胞和免疫球蛋白沉积在炎症性肿瘤细胞环境中的重要作用已在多种癌症中得到认可，并且在我们的炎症相关致癌作用的小鼠模型中也得到了重现：上皮细胞中表达爱泼斯坦-巴尔病毒癌基因LMP1的转基因小鼠。同样，在几种自身免疫性疾病中，免疫球蛋白沉积是疾病过程中的一个关键潜在事件。然而，在大多数情况下，自身抗原尚不清楚。在其他研究中，已观察到多种自身免疫性疾病和众多癌症中酶活性无活性的哺乳动物几丁质酶样蛋白（CLP）过表达，其表达与预后不良相关，尽管这些蛋白的功能在很大程度上尚不清楚。我们现在将这些观察结果联系起来，证明CLP的过表达使其在致癌进展过程中成为自身抗原性的靶标。我们表明，CLP、Chi3L1、Chi3L3 / YM1和Chi3L4 / YM2在肿瘤发生前的早期转基因表皮中大量过表达并分泌到血清中。在血清中检测到对CLP有反应的免疫球蛋白G，并沉积在增生组织中，该组织继而发炎并逐渐发育异常。CLP在转基因和野生型小鼠的化学致癌物促进的病变中也上调。相关的活性几丁质酶Chit1和AMCase的表达在炎症细胞浸润后增加。在这个模型中，这3种CLP是组织沉积免疫球蛋白的自身抗原，我们认为其在促进炎症相关致癌作用中起因果作用。这可能反映了它们促进组织重塑和放大免疫反应的正常、良性功能。它们在致癌过程中的诱导以及随之而来的自身抗原性提供了致癌事件与随后炎症之间缺失的环节。这项研究将CLP确定为限制癌症炎症以及潜在的自身免疫性疾病的重要且新的治疗靶点。
