The activity of the peroxisome-proliferator-activated receptor (PPAR) family members has been implicated in various tumour types, although the evidence for one of these proteins — PPARβ/δ — has been contradictory. Raymond DuBois and colleagues have therefore used a mouse model of colorectal cancer, along with a Pparβ/δ selective agonist, to more clearly demonstrate the role of Pparβ/δ in tumour growth.
PPARs are a family of ligand-activated transcription factors that function as nuclear hormone receptors. PPARβ/δ is involved in development, wound healing, fatty-acid metabolism and repression of the inflammatory response. More importantly, the expression and activity of PPARβ/δ are increased after loss of the adenomatous polyposis coli (APC) tumour suppressor, which implicates it in the pathogenesis of colorectal cancer. To support this, a study showed that loss of both PPARβ/δ alleles from a colorectal cancer cell line slowed tumour growth. A separate study, however, reported that disruption of Pparβ/δ did not affect polyp formation in Apcmin mice — a model of intestinal polyposis that progresses to colorectal cancer, in which Apc is mutated. DuBois and colleagues therefore tested another approach to this problem — they treated Apcmin mice with the selective Pparβ/δ agonist GW501516.
Pparβ/δ is expressed primarily in the intestinal epithelial cells of both the normal intestinal epithelia and adenomas of Apcmin mice. Treating these mice with GW501516 led to a twofold increase in polyp number in the small intestine, but no change in the number of colon polyps. The mice treated with the Pparβ/δ agonist also showed a fivefold increase in polyps larger than 2 mm, so Pparβ/δ activation seems to affect the rate of polyp growth more than polyp formation. The polyps in these mice also had a slightly higher degree of dysplasia, indicating a more advanced stage of progression.
How does Pparβ/δ activation promote tumour growth? Although GW501516 had no effect on proliferation of colorectal cancer cells in vitro, it suppressed apoptosis in a dose-dependent manner. DuBois concluded that Pparβ/δ stimulates the growth and development of intestinal adenomas by activating anti-apoptotic pathways in intestinal epithelial cells.
This finding has important implications for the clinic, as activating ligands of PPARβ/δ (including GW501516) are in the later stages of development as drugs to treat dyslipidaemia syndromes, obesity and atherosclerosis. PPARβ/δ agonists should be administered with caution, as they might increase the risk of cancer in individuals with familial adenomatous polyposis — a disease in which APC mutations lead to a high incidence of colorectal cancer.
References
ORIGINAL RESEARCH PAPER
Gupta, R. A. et al. Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-δ accelerates intestinal adenoma growth. Nature Med. 1 Feb 2004 (doi: 10.1038/nm993)
FURTHER READING
Michalik, L., Desvergne, B. & Wahli, W. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nature Rev. Cancer 4, 61–70 (2004)
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Novak, K. Conflict resolution. Nat Rev Cancer 4, 169 (2004). https://doi.org/10.1038/nrc1304
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DOI: https://doi.org/10.1038/nrc1304