Oral Presentation 14th International Biennial Conference on Metastasis Research 2012

Colon cancer microenvironment that helps invasion and metastasis: studies using mouse models (#1)

Makoto Mark Taketo 1
  1. Kyoto Univ. Grad. Sch. Medicine, Kyoto, Japan

Owing to early detection and intervention, most patients of early stage colon cancer are now cured completely. However, colon cancer is still lethal for many patients whose disease has progressed to the metastatic stage. Colon cancer appears to progress through a series of multi-step genetic/epigenetic changes via the adenoma-carcinoma sequence.

We earlier constructed ApcD716 knockout mice, a model for human FAP. Using the model, we found the polyp adenoma morphogenetic mechanisms, and demonstrated the role of COX-2 in adenoma expansion. Importantly, we found that COX-2 is expressed exclusively in the fibroblasts of tumor stroma rather than in the epithelial cells at this early stage of tumorigenesis.

To study the role of TGF-b signaling in colon cancer, we introduced a Smad4 knockout mutation into the ApcD716 knockout mice, and found that their intestinal polyp adenomas become locally invasive adenocarcinomas. This was caused by recruitment of bone marrow-derived CCR1+ cells that produce MMP9. Furthermore, essentially the same mechanism appears to help disseminated colon cancer cells to colonize in the liver. Interestingly, treatment of the Apc/Smad4 mice with a CCR1 inhibitor suppressed the metastatic colonization of colon cancer cells in the liver.

To investigate the mechanisms that stimulate metastasis by colon cancer epithelium, we have screened for and found a novel metastasis suppressor Aes that has turned out to be an endogenous inhibitor of Notch signaling. In colon cancer tissues, cancer cells express abundant Notch receptors whereas their ligands such as Jagged1 and Delta4 are expressed by the tumor stroma on vascular endothelial cells, smooth muscle layers and infiltrating macrophages.

These results collectively indicate that from early stages of colon cancer progression, tumors expand, invade and metastasize through the interactions with their microenvironment in multiple modes.