Transforming growth factor-beta1 and regulators of apoptosis.
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.
Sulkowski
Stanislaw
S
Department of General Pathomorphology, Collegium Pathologicum, Medical University of Bialystok, Bialystok, Poland. sulek@zeus.amb.edu.pl
Wincewicz
Andrzej
A
Sulkowska
Mariola
M
Koda
Mariusz
M
D017209:Apoptosis; D003106:Colon / Q000737:chemistry / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000737:chemistry; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D012007:Rectum / Q000737:chemistry / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis*; D051020:bcl-X Protein / Q000096:biosynthesis*
C494826:BAX protein, human; C494811:BCL2L1 protein, human; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein