Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy;
Aging Research Center, G. D'Annunzio University Foundation, 66013 Chieti, Italy;
J Immunol. 2014 Jun 1;192(11):5434-41. doi: 10.4049/jimmunol.1301248. Epub 2014 Apr 30.
Perforin (pfp)-mediated cytotoxicity is one of the principal immunosurveillance mechanisms involved in the fight against cancer. However, its importance in spontaneous epithelial cancer is still poorly defined. In this study, we use a realistic mouse model that displays many features that are equivalent to human pathology to evaluate the role of pfp-dependent immunosurveillance by comparing tumor progression in rat ERBB-2 (neu) transgenic, pfp-proficient (neu(+)/pfp(+)) or pfp-deficient (neu(+)/pfp(-)) BALB/c male mice. Adult neu(+)/pfp(+) males developed poorly differentiated salivary carcinomas, whereas neu(+)/pfp(-) males displayed their salivary carcinomas noticeably earlier and showed zones of more highly differentiated tumor, indicating that pfp-mediated immunosurveillance is able not only to delay the growth kinetic of an aggressive epithelial tumor, but also to shape its histology. The role of pfp-mediated immunosurveillance appeared to be of even more dramatic importance against the less aggressive male mammary carcinomas. In neu(+)/pfp(+) males, the incidence of mammary carcinomas was a sporadic and late event. In contrast, in neu(+)/pfp(-) males their incidence was four-fold higher. This higher cancer incidence was associated with a 2-fold higher occurrence of persisting mammary remnants, a major risk factor for mammary cancer in male mice, and one that would appear to be due to pfp's previously unidentified involvement in male mammary gland rejection during embryogenesis. This work thus provides further proof of the complex role that the immune system plays in the body and gives new insight into the pathogenesis of epithelial tumors, demonstrating that the penetrance and malignancy of a tumor may be dramatically affected by pfp-dependent mechanisms.
穿孔素（pfp）介导的细胞毒性是参与抗癌的主要免疫监视机制之一。然而，其在自发性上皮癌中的重要性仍未得到充分定义。在这项研究中，我们使用一种现实的小鼠模型，该模型显示出许多与人类病理学等效的特征，通过比较在大鼠 ERBB-2（neu）转基因、pfp 有功能（neu(+)/pfp(+）或 pfp 缺失（neu(+)/pfp(-））BALB/c 雄性小鼠中的肿瘤进展，来评估 pfp 依赖性免疫监视的作用。成年 neu(+)/pfp(+)雄性小鼠发展为低分化唾液腺癌，而 neu(+)/pfp(-)雄性小鼠则更早地显示出唾液腺癌，并且显示出更高分化的肿瘤区域，这表明 pfp 介导的免疫监视不仅能够延迟侵袭性上皮肿瘤的生长动力学，还能够塑造其组织学。pfp 介导的免疫监视的作用对于侵袭性较低的男性乳腺肿瘤似乎更为重要。在 neu(+)/pfp(+)雄性小鼠中，乳腺肿瘤的发生率是零星的和晚期的事件。相比之下，在 neu(+)/pfp(-)雄性小鼠中，其发生率高四倍。这种更高的癌症发生率与持续存在的乳腺残余物的两倍高发生率相关，这是雄性小鼠乳腺癌的一个主要危险因素，这似乎是由于 pfp 以前未被识别的参与胚胎发生期间雄性乳腺的排斥。这项工作进一步证明了免疫系统在体内所起的复杂作用，并为上皮肿瘤的发病机制提供了新的见解，表明肿瘤的穿透性和恶性程度可能会受到 pfp 依赖机制的显著影响。
