A SUBSET OF METASTATIC HUMAN COLON CANCERS EXPRESSES ELEVATED LEVELS OF TRANSFORMING-GROWTH-FACTOR BETA-1

Although transforming growth factor (TGF)-beta 1 is a potent growth in hibitor of normal epithelial cells including colonocytes, TGF-beta 1 h as also been implicated as an enhancer of colon cancer metastasis. Dec reasing TGF-beta 1 protein levels in the metastatic U9 colon cancer ce ll line by antisense methodology decreased both U9 cell metastasis to the liver and s.c. tumor formation in a nude mouse system, and the tum ors that did arise had regained TGF-beta 1 expression (F, Huang et at, Cell Growth Differ., 6: 1635-1642, 1995), In addition, in a clinical immunohistochemistry study, colon cancers with elevated TGF-beta 1 pro tein levels were found to be 18 times more likely to recur as distant metastases than colon cancers expressing low TGF-beta 1 levels, after resection of the primary tumor (E. Friedman et al., Cancer Epidemiol, Biomark, Prev., 4: 549-554, 1995). Because both studies implicated TGF -beta 1 in colon cancer metastasis, we wished to know whether a select ion bias for TGF-beta 1 was maintained in metastatic cells or was only a property of the primary site tumors that were likely to metastasize , TGF-beta 1 levels were measured using two different antibodies in pa ired primary site cancers and their metastases by immunohistochemistry and, in selected cases, by Western blot analysis. In 16 of 21 cases ( 76%) with antibody G and 23 of 31 cases (74%) with antibody P, higher expression of TGF-beta 1 was found in colon cancer cells invading loca l lymph nodes compared ,vith primary site colon cancer cells, or (2 an d 6 cases, respectively) high TGF-beta 1 expression in the primary sit e cancer was maintained in invasive cells. Analysis by Western blottin g using both antibodies also demonstrated that higher levels of TGF-be ta 1 protein were found in metastases compared with the primary site t umor or normal tissue. Additional cases of paired primary site colon c ancer, local lymph node metastases, and cancer cells metastasizing to distant sites were examined. In six of eight such cases (75%), TGF-bet a 1 levels were increased in both invasive cell populations compared w ith the primary site cancer (five cases), or high levels in the primar y site cancer were maintained in the metastatic cells (one case). Thes e data suggest that TGF-beta 1 plays a role in promoting colon cancer metastasis throughout the metastatic process in roughly 75% of cases. TGF-beta 1 may increase metastasis by paracrine mechanisms, such as su ppression of local immune response or increased angiogenesis, as was s een with the U9 cell line. In those cancers with nonmutated TGF-beta r eceptors and nonmutated smad proteins like U9 cells, TGF-beta 1 could also act in an autocrine manner to increase invasion by increasing cel l motility (Hsu et al,, Cell Growth Differ., 5: 267-275, 1994).