Sulkowski Stanislaw, Wincewicz Andrzej, Sulkowska Mariola, Koda Mariusz
Department of General Pathomorphology, Collegium Pathologicum, Medical University of Bialystok, Bialystok, Poland.
Ann N Y Acad Sci. 2009 Aug;1171:116-23. doi: 10.1111/j.1749-6632.2009.04686.x.
Growth inhibitory function of transforming growth factor-beta1 (TGF-beta1) is abolished in colorectal cancer cells as a consequence of mutations of various downstream signaling agents, such as p53, which fail to respond to TGF-beta1 stimulation. TGF-beta1 could also suppress T-cell-mediated anticancer immunity. We aimed at a comparison between cancer expressions of apoptosis regulators, such as p53, BCL-2-associated X protein (Bax), and B-cell leukemia/lymphoma extra-long protein (Bcl-xL), with TGF-beta1 in malignant and adjacent inflammatory cells in immunohistochemical evaluations of 108 colorectal cancers. Cytoplasm compartment of cancer cells was overloaded with TGF-beta1, and 87% of all cancers were TGF-beta1 positive (94/108). A very strong pattern of staining was detected for TGF-beta1 in cytoplasm of inflammatory cells at tumor margins. TGF-beta1 correlated with Bcl-xL and Bax in all colorectal cancers (P < 0.001, r= 0.473 and P < 0.001, r= 0.435, respectively) and subgroups of different clinicopathological features, especially in deeply invading cancers (pT3+pT4) instead of superficially growing tumors (pT1+pT2). Expression of TGF-beta1 in inflammatory infiltrates correlated with immunoreactivities to Bcl-xL of cancer cells (P= 0.024, r= 0.217). TGF-beta1 did not associate with p53, nor did TGF-beta1 of inflammatory cells correlate with Bax expression in cancer cells. Lack of correlations between TGF-beta1 and p53 proteins could indicate mutations at the TGF-beta1-dependent apoptotic pathway. Dominant positive linkage between TGF-beta1 and Bcl-xL and selective lack of association with Bax suggest TGF-beta1 could support colorectal cancer cell survival. The pattern of correlations seems to confirm a remarkable shift from TGF-beta1-dependent suppression of cancer growth by apoptosis to inhibition of anticancer immunity by TGF-beta1.
由于各种下游信号分子（如p53）发生突变，对转化生长因子-β1（TGF-β1）刺激无反应，导致TGF-β1在结肠直肠癌细胞中的生长抑制功能丧失。TGF-β1还可抑制T细胞介导的抗癌免疫。我们旨在通过对108例结肠直肠癌进行免疫组织化学评估，比较凋亡调节因子（如p53、BCL-2相关X蛋白（Bax）和B细胞白血病/淋巴瘤超长蛋白（Bcl-xL））在恶性细胞和相邻炎症细胞中的表达与TGF-β1的关系。癌细胞的细胞质中TGF-β1含量过高，所有癌症中有87%（94/108）的TGF-β1呈阳性。在肿瘤边缘炎症细胞的细胞质中检测到TGF-β1的染色模式非常强烈。在所有结肠直肠癌中，TGF-β1与Bcl-xL和Bax相关（分别为P < 0.001，r = 0.473和P < 0.001，r = 0.435），以及不同临床病理特征的亚组，特别是在深度浸润癌（pT3 + pT4）而非浅表生长肿瘤（pT1 + pT2）中。炎症浸润中TGF-β1的表达与癌细胞对Bcl-xL的免疫反应性相关（P = 0.024，r = 0.217）。TGF-β1与p53不相关，炎症细胞中的TGF-β1也与癌细胞中的Bax表达不相关。TGF-β1与p53蛋白之间缺乏相关性可能表明TGF-β1依赖性凋亡途径发生了突变。TGF-β1与Bcl-xL之间的显性正相关以及与Bax选择性缺乏关联表明TGF-β1可能支持结肠直肠癌细胞的存活。这种相关性模式似乎证实了从TGF-β1依赖性通过凋亡抑制癌症生长到TGF-β1抑制抗癌免疫的显著转变。
