Analysis of the TGF-beta signaling pathway in genomically stable murine colon tumors

Date of Completion

January 2003

Keywords

Health Sciences, Pharmacology

Degree

Ph.D.

Abstract

The azoxymethane (AOM)-mouse model is widely used to study the multistage progression of sporadic colorectal cancers (CRCs) in humans and to search for chemopreventive and curative agents. However, unlike human cancers, invasion and metastasis are seldom observed in this model and the animals begin to die at a younger age (∼7 months) owing to a heavy tumor burden following carcinogen treatment. We tested the possibility of whether a reduction in tumor incidence may allow the animals to live longer and thereby provide the tumors sufficient time to acquire an invasive potential. However, our results in AOM-treated A/J mice suggest that the non-invasive phenotype may in part be due to attenuated proteolysis in the tumor microenvironment rather than a time-dependent variable. To better define the genetic events associated with tumorigenesis in this murine model, we analyzed the tumors for chromosomal (CIN) and microsatellite (MSI) instabilities, two important pathways of genomic instability that play a critical role in initiation, progression and metastasis of human CRCs. Using molecular cytogenetic techniques, we show that carcinogen-induced tumors are genomically stable, which, in turn, may also explain to a certain extent the behaviorally benign nature of these tumors. Similar to our findings, recent studies in humans also suggest that mechanisms other than CIN or MSI may play a role in the pathogenesis of colon cancers. ^ Accordingly, we analyzed the status of the TGF-β signaling pathway, which is implicated in the development of both genetically stable and unstable CRCs in humans, in our model. In fact, we found a downregulation of TGF-β type II receptor in addition to a defective processing of the latent TGF-β ligand in AOM-induced tumors. Consistent with this, a dysregulation in TGF-β-specific target genes was observed in these tumors. Taken together, we propose that an aberrant TGF-β signaling pathway may in part facilitate the development of genetically stable tumors during chemical carcinogenesis. ^

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