Deregulation of tumor angiogenesis and blockade of tumor growth in PPARβ-deficient mice

Abstract

The peroxisome proliferator‐activated receptor‐β (PPARβ) has been implicated in tumorigenesis, but its precise role remains unclear. Here, we show that the growth of syngeneic Pparb wild‐type tumors is impaired in Pparb−/− mice, concomitant with a diminished blood flow and an abundance of hyperplastic microvascular structures. Matrigel plugs containing pro‐angiogenic growth factors harbor increased numbers of morphologically immature, proliferating endothelial cells in Pparb−/− mice, and retroviral transduction of Pparb triggers microvessel maturation. We have identified the Cdkn1c gene encoding the cell cycle inhibitor p57Kip2 as a PPARβ target gene and a mediator of the PPARβ‐mediated inhibition of cell proliferation, which provides a possible mechanistic explanation for the observed tumor endothelial hyperplasia and deregulation of tumor angiogenesis in Pparb−/− mice. Our data point to an unexpected essential role for PPARβ in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels.

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines

“…These observations are consistent with recent findings made in other human cancer cell lines (Hollingshead et al 2007a), as well as numerous reports linking PPARβ/δ with inducing terminal differentiation and/or inhibiting cell growth (Ali et al 2005;Aung et al 2006;Burdick et al 2007;Fukumoto et al 2005;Hollingshead et al 2007a;Kim et al 2004;Kim et al 2006;Kim et al 2005;Man et al 2007;Marin et al 2006;Martinasso et al 2006;Matthiessen et al 2005;Michalik et al 2001;Müller-Brüsselbach et al 2007;Nadra et al 2006;Ou et al 2007;Peters et al 2000;Planavila et al 2005;Schmuth et al 2004;Tan et al 2001;Teunissen et al 2007;Varnat et al 2006;Westergaard et al 2001). The relatively modest activation of PPARβ/δ in both UACC903 and MCF7 cells as shown by increased mRNA encoding ANGPTL4 shows that these cells are not highly responsive to PPARβ/δ ligands as compared to other cells such as keratinocytes.…”

“…There is also strong evidence that ligand activation of PPARβ/δ promotes terminal differentiation in intestinal epithelium, breast and colon cancer cell lines, trophoblasts and primary keratinocytes (Aung et al 2006;Burdick et al 2007;Kim et al 2006;Marin et al 2006;Nadra et al 2006;Schmuth et al 2004;Tan et al 2001;Varnat et al 2006;Westergaard et al 2001). Evidence from a large number of independent laboratories also shows that cell growth is inhibited by PPARβ/δ and its ligands in colonocytes, keratincytes, cardiomyocytes, fibroblasts, endothelial cells and a variety of cancer cell lines (Ali et al 2005;Aung et al 2006;Burdick et al 2007;Fukumoto et al 2005;Hollingshead et al 2007a;Kim et al 2004;Kim et al 2006;Kim et al 2005;Man et al 2007;Marin et al 2006;Martinasso et al 2006;Matthiessen et al 2005;Michalik et al 2001;Müller-Brüsselbach et al 2007;Nadra et al 2006;Ou et al 2007;Peters et al 2000;Planavila et al 2005;Schmuth et al 2004;Tan et al 2001;Teunissen et al 2007;Varnat et al 2006;Westergaard et al 2001). Given the potential of PPARβ/δ ligands as therapeutic agents, it is of great importance to determine the effect of ligand activation of PPARβ/δ on cell growth in vitro and in vivo.…”

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

“…11,[21][22][23] Significant roles for PPAR␤/␦ in many tissues including skin, colon, and liver have been elucidated using this mouse line. [9][10][11]15,[21][22][23][24][25] The animals were fed a standard rodent chow with ad libitum access to drinking water. Wild-type and PPAR␤/␦-null mice were administered AOM (10 mg/kg body weight) by intraperitoneal injection once per week for either 1, 3, 5, or 10 weeks.…”

p57: A multifunctional protein in cancer (Review)

“…The expression of p57 in tumor cells is required for blood vessel formation and tumor growth in PPARß -/-mice. When expressed in the tumor cells, p57 inhibits tumorigenesis by a direct inhibitory effect of tumor cell proliferation, while its expression in tumor endothelial cells is required for blood vessel formation and thus tumor growth (112). These results suggest that the loss or subversion of the regulatory mechanisms governing p57 expression may lead to the specific loss of the tumor suppressive function of p57 while maintaining the oncogenic ones.…”