Smad3 Deficiency Promotes Tumorigenesis in the Distal Colon of ApcMin/+ Mice

Abstract

Colorectal cancer, one of the most common human malignancies in the Western world, is often subdivided based on tumor location in either the distal or proximal colon. Several mouse models have been developed to study human colorectal cancer, but few display this clear distinction between the two colonic locations. By crossing Apc Min/+ and Smad3 mutant mice, we showed that combined activation of the Wnt pathway and attenuation of the transforming growth factor-B (TGF-B) pathway causes high multiplicity and rapid onset of invasive tumorigenesis almost exclusively in the distal colon, closely mimicking the familial adenomatous polyposis (FAP) disease and consisting with distinct colorectal cancer etiologies based on tumor location. Transcriptional profiling revealed higher expression of several TGF-B activators in the normal distal mucosa than in proximal mucosa, suggesting a stronger reliance on TGF-B-mediated growth control in the distal than in the proximal colon. ApcÀ/À mice provide an alternative model to Apc Min/+ mice to study FAP and distal sporadic colorectal cancer. This model will be useful in dissecting mechanistic and etiologic differences between proximal and distal colonic cancer, whereas the confinement of tumorigenesis to the distal colon offers unique advantages in monitoring tumor progression by in vivo imaging. (Cancer Res 2006; 66(17): 8430-8)

Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas

“…Rab25 loss also led to a marked acceleration in invasive colon tumor formation in Smad3 +/-mice. The general phenotype of the Smad3 +/-;Rab25 -/-mice was similar to previously reported accelerated pathology in Apc Min/+ ;Smad3 -/-mice (33). The Apc Min/+ ;Smad3 -/-mice also showed more rapid and extensive colon tumor formation.…”

rNAPc2 Inhibits Colorectal Cancer in Mice through Tissue Factor

“…In addition, tumors in Apc Min/+ mice do not appear to metastasize (15,20). Therefore, genetic models, such as Apc Min/+ Smad3 -/-and Apc Min/+ Ephb3 -/-mice in which tumorigenesis is accelerated in the colon and rectum, may represent a clinically more relevant colorectal cancer model to further elaborate the antitumor activity of rNAPc2 (43,44).…”

Targeted Imaging of Colonic Tumors in Smad3−/− Mice Discriminates Cancer and Inflammation

“…Multiple methods for noninvasive assessment of intestinal tumors in mouse models have emerged over the past several years (5,6,22). The method presented here based on targeting PBR expression combines the low-cost, high-throughput advantages of optical methods based on bioluminescence, yet avoids the requirement for a reporter transgene enhancing the potential for translational usefulness.…”