Growth and inhibition of intestinal tumors.

摘要

During the multistep transformation of normal epithelial cells into colorectal cancer (CRC), cells acquire a limited set of essential features that move the cells toward malignancy. Two of these fundamental properties acquired early during the CRC latency period include cell autonomous dysregulation of growth control and the ability to trigger neoangiogenesis. Delineating and therapeutically targeting such molecular events that underlie the pre-malignancy period could lead to more effective intervention strategies against CRC. Recently, genes that may play key roles in each of these two early events were identified. Preliminary work identified a group of tumor endothelial marker (TEM) genes that are selectively expressed on vasculature during neoangiogenesis in CRC, but are not expressed on resting vasculature. Also, preliminary work suggests that truncating adenomatous polyposis coli (Apc) gene mutations, a hallmark of CRC initiation, trigger Cdk4 dysregulation in the intestinal stem cell compartment/crypt. Cdk4 activity plays an important role early in tumorigenesis.; To assess the functional role of Tem1, we generated Tem1-/- mice. Tem1 disruption did not cause any lethal defects or interfere with development or fertility. Skin wound healing as well as the growth of tumors is not dependent on Tem1 when implanted in subcutaneous sites. However, Tem1 -/- mice had significantly slower growing tumors that were less invasive when implanted at orthotopic abdominal sites compared to wild type mice. This indicates that stromal factors can influence tumor growth and aggressiveness and that this can vary with anatomic site. To determine the potential role of Cdk4 as a target for cancer therapy and prevention, a combination of genetic and dietary manipulation were performed to assess the effects of reduced Cdk4 on polyp Apc-/+ mice. Loss of Apc function appears to be a very early if not initiating step in almost all human colorectal cancers. Genetic deficiency of Cdk4 in compound mutant mice (Cdk4-/-Apc -/+) decreases tumor number and size of polyps compared to Apc-/+ mice. Also, vitamin D analogue and silibinin were found to cause hypophosphorylation of Rb protein (a Cdk4 target), decrease cyclin D1 levels (an activating Cdk4 binding partner), inhibit proliferation of intestinal crypt epithelial cells, increase apoptosis, and significantly reduce the number of polyps in Apc-/+ mice.; Together these data suggest that Tem1 and Cdk4 are viable targets in distinct pathways for tumor therapy and prevention strategies and may therefore be useful in developing combinatorial approaches against human colorectal cancer.