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Contextual effects of transforming growth factor beta on the tumorigenicity of human colon carcinoma cells.
Cancer Res 1999; 59(18):4725-31CR

Abstract

Transforming growth factor betas (TGF-betas) are a growth factor family with negative autocrine growth functions for most epithelial cells including colon carcinoma cell lines. Both type I (RI) and type II (RII) transmembrane TGF-beta receptors have been shown to be indispensable for TGF-beta-mediated cell growth regulation. Previous studies using different model systems have shown that both overexpression of TGF-beta1 and transfection of antisense TGF-beta1 to reduce TGF-beta1 expression could lead to increased tumorigenicity. These results are seemingly contradictory and suggest that effects of TGF-beta modulation on malignant properties of cancer cells may be contextual. This study addresses this issue using human colon carcinoma cells (CBS and FET) to determine the effects of modulation of the various components of the TGF-beta system on in vitro and in vivo growth properties in two independent isogenic models of colon carcinoma. Cells were stably transfected with a tetracycline-repressible RII expression vector (CBS4-RII), a tetracycline-repressible expression vector containing a truncated RII cDNA lacking the serine/threonine kinase domain (CBS4-deltaRII and FET6-deltaRII), or with a vector containing the TGF-beta1 cDNA (CBS4-beta1S and FET-beta1S). Expression of the truncated RII reduced TGF-beta sensitivity, whereas overexpression of RII increased TGF-beta sensitivity. TGF-beta overexpression did not affect TGF-beta response. In vivo tumorigenicity assays revealed that CBS4-RII cells had lower tumorigenicity than control cells, whereas CBS4-deltaRII and CBS4-beta1S had higher tumorigenicity than controls. The CBS4 cells are poorly tumorigenic in athymic mice, and the wild-type FET6 cells are nontumorigenic. FET6-deltaRII cells formed rapidly growing tumors, and FET-beta1S cells also formed tumors. These data illustrate the paradoxical tumor-promoting and -suppressing effects of TGF-beta signaling activity in two isogenic model systems from human colon carcinomas, thus demonstrating that the effects of modulation of TGF-beta expression or TGF-beta signaling capability affects malignancy in a contextual manner.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, Medical College of Ohio at Toledo, 43614-2595, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10493532

Citation

Ye, S C., et al. "Contextual Effects of Transforming Growth Factor Beta On the Tumorigenicity of Human Colon Carcinoma Cells." Cancer Research, vol. 59, no. 18, 1999, pp. 4725-31.
Ye SC, Foster JM, Li W, et al. Contextual effects of transforming growth factor beta on the tumorigenicity of human colon carcinoma cells. Cancer Res. 1999;59(18):4725-31.
Ye, S. C., Foster, J. M., Li, W., Liang, J., Zborowska, E., Venkateswarlu, S., ... Willson, J. K. (1999). Contextual effects of transforming growth factor beta on the tumorigenicity of human colon carcinoma cells. Cancer Research, 59(18), pp. 4725-31.
Ye SC, et al. Contextual Effects of Transforming Growth Factor Beta On the Tumorigenicity of Human Colon Carcinoma Cells. Cancer Res. 1999 Sep 15;59(18):4725-31. PubMed PMID: 10493532.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Contextual effects of transforming growth factor beta on the tumorigenicity of human colon carcinoma cells. AU - Ye,S C, AU - Foster,J M, AU - Li,W, AU - Liang,J, AU - Zborowska,E, AU - Venkateswarlu,S, AU - Gong,J, AU - Brattain,M G, AU - Willson,J K, PY - 1999/9/24/pubmed PY - 1999/9/24/medline PY - 1999/9/24/entrez SP - 4725 EP - 31 JF - Cancer research JO - Cancer Res. VL - 59 IS - 18 N2 - Transforming growth factor betas (TGF-betas) are a growth factor family with negative autocrine growth functions for most epithelial cells including colon carcinoma cell lines. Both type I (RI) and type II (RII) transmembrane TGF-beta receptors have been shown to be indispensable for TGF-beta-mediated cell growth regulation. Previous studies using different model systems have shown that both overexpression of TGF-beta1 and transfection of antisense TGF-beta1 to reduce TGF-beta1 expression could lead to increased tumorigenicity. These results are seemingly contradictory and suggest that effects of TGF-beta modulation on malignant properties of cancer cells may be contextual. This study addresses this issue using human colon carcinoma cells (CBS and FET) to determine the effects of modulation of the various components of the TGF-beta system on in vitro and in vivo growth properties in two independent isogenic models of colon carcinoma. Cells were stably transfected with a tetracycline-repressible RII expression vector (CBS4-RII), a tetracycline-repressible expression vector containing a truncated RII cDNA lacking the serine/threonine kinase domain (CBS4-deltaRII and FET6-deltaRII), or with a vector containing the TGF-beta1 cDNA (CBS4-beta1S and FET-beta1S). Expression of the truncated RII reduced TGF-beta sensitivity, whereas overexpression of RII increased TGF-beta sensitivity. TGF-beta overexpression did not affect TGF-beta response. In vivo tumorigenicity assays revealed that CBS4-RII cells had lower tumorigenicity than control cells, whereas CBS4-deltaRII and CBS4-beta1S had higher tumorigenicity than controls. The CBS4 cells are poorly tumorigenic in athymic mice, and the wild-type FET6 cells are nontumorigenic. FET6-deltaRII cells formed rapidly growing tumors, and FET-beta1S cells also formed tumors. These data illustrate the paradoxical tumor-promoting and -suppressing effects of TGF-beta signaling activity in two isogenic model systems from human colon carcinomas, thus demonstrating that the effects of modulation of TGF-beta expression or TGF-beta signaling capability affects malignancy in a contextual manner. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/10493532/Contextual_effects_of_transforming_growth_factor_beta_on_the_tumorigenicity_of_human_colon_carcinoma_cells_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10493532 DB - PRIME DP - Unbound Medicine ER -