Kim Byung-Gyu, Li Cuiling, Qiao Wenhui, Mamura Mizuko, Kasprzak Barbara, Anver Miriam, Wolfraim Lawrence, Hong Suntaek, Mushinski Elizabeth, Potter Michael, Kim Seong-Jin, Fu Xin-Yuan, Deng Chuxia, Letterio John J
Laboratory of Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature. 2006 Jun 22;441(7096):1015-9. doi: 10.1038/nature04846.
SMAD4 (MAD homologue 4 (Drosophila)), also known as DPC4 (deleted in pancreatic cancer), is a tumour suppressor gene that encodes a central mediator of transforming growth factor-beta signalling. Germline mutations in SMAD4 are found in over 50% of patients with familial juvenile polyposis, an autosomal dominant disorder characterized by predisposition to hamartomatous polyps and gastrointestinal cancer. Dense inflammatory cell infiltrates underlay grossly normal appearing, non-polypoid colonic and gastric mucosa of patients with familial juvenile polyposis. This prominent stromal component suggests that loss of SMAD4-dependent signalling in cells within the epithelial microenvironment has an important role in the evolution of intestinal tumorigenesis in this syndrome. Here we show that selective loss of Smad4-dependent signalling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumours arising within the colon, rectum, duodenum, stomach and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4(-/-) T cells produce abundant T(H)2-type cytokines including interleukin (IL)-5, IL-6 and IL-13, known mediators of plasma cell and stromal expansion. The results support the concept that cancer, as an outcome, reflects the loss of the normal communication between the cellular constituents of a given organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours.
SMAD4（果蝇MAD同源物4），也称为DPC4（胰腺癌缺失基因），是一种肿瘤抑制基因，编码转化生长因子-β信号传导的核心介质。超过50%的家族性幼年性息肉病患者存在SMAD4种系突变，这是一种常染色体显性疾病，其特征是易患错构瘤性息肉和胃肠道癌。在家族性幼年性息肉病患者大体外观正常、无息肉的结肠和胃黏膜下有密集的炎性细胞浸润。这种显著的基质成分表明，上皮微环境中细胞内SMAD4依赖性信号传导的缺失在该综合征肠道肿瘤发生的演变中起重要作用。我们在此表明，T细胞中Smad4依赖性信号传导的选择性缺失会导致小鼠整个胃肠道自发发生上皮癌，而Smad4基因的上皮特异性缺失则不会。在结肠、直肠、十二指肠、胃和口腔内发生的肿瘤富含基质，有密集的浆细胞浸润。Smad4（-/-）T细胞产生大量TH2型细胞因子，包括白细胞介素（IL）-5、IL-6和IL-13，这些是已知的浆细胞和基质扩张介质。这些结果支持了癌症作为一种结果反映了给定器官细胞成分之间正常通讯缺失的概念，并表明Smad4缺陷型T细胞最终向其基质和上皮邻居传递了错误信息。
