Loss of GDF-15 Abolishes Sulindac Chemoprevention in the ApcMin/+ Mouse Model of Intestinal Cancer

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2009 Sep 29

PMID 19784846

Citations 23

Authors

Teresa A Zimmers

Juan C Gutierrez

Leonidas G Koniaris

Affiliations

Soon will be listed here.

Abstract

Background: Growth-differentiation factor (GDF)-15, a member of the TGF-beta superfamily, is potently induced in the intestine following mechanical injury, genotoxic insult and following non-steroidal anti-inflammatory drugs (NSAIDs) exposure. GDF-15 expression correlates with apoptosis in intestinal cells and has been implicated in the pathogenesis of colorectal cancer formation and the anti-tumor effects of NSAIDs. We sought to determine the effect of loss of Gdf15 on animal tumor models of hereditary colon cancer and in the NSAID-mediated prevention of heritable colorectal cancer.

Methods: GDF-15 null (Gdf15 (-/-)) mice and mice with the genetic mutation found in hereditary poliposis coli, Apc ( min/+ ) were bred. Gdf15 ( -/- ), Apc ( min/+ ) and Gdf15 ( +/+ ), Apc ( min/+ ) mice were generated.

Results: In Gdf15 ( -/- ), Apc ( min/+ ) mice, intestinal neoplasia formation rate and size were indistinguishable from that in Gdf15 ( +/+ ), Apc ( min/+ ) mice. Sulindac chemoprotection activity although potent in Gdf15 ( +/+ ), Apc ( min/+ ) mice was abolished in Gdf15 ( -/- ), Apc ( min/+ ) mice.

Conclusions: These results demonstrate in a murine model that GDF-15 does not significantly regulate heritable in vivo intestinal carcinogenesis but does mediate sulindac chemoprevention in heritable colon cancer. These data suggest that the use of GDF-15 activated signaling pathways may allow improved chemoprevention and therapies for colorectal cancer.

Citing Articles

GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma.

Wang Z, He L, Li W, Xu C, Zhang J, Wang D J Immunother Cancer. 2021; 9(9).

PMID: 34489334 PMC: 8422483. DOI: 10.1136/jitc-2021-002787.

Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15.

Cimino I, Kim H, Tung Y, Pedersen K, Rimmington D, Tadross J Proc Natl Acad Sci U S A. 2021; 118(27).

PMID: 34187898 PMC: 8271778. DOI: 10.1073/pnas.2106868118.

GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer.

Ahmed D, Isnard S, Lin J, Routy B, Routy J J Cancer. 2021; 12(4):1125-1132.

PMID: 33442410 PMC: 7797663. DOI: 10.7150/jca.50376.

Growth differentiation factor-15 slows the growth of murine prostate cancer by stimulating tumor immunity.

Husaini Y, Tsai V, Manandhar R, Zhang H, Lee-Ng K, Lebhar H PLoS One. 2020; 15(6):e0233846.

PMID: 32502202 PMC: 7274405. DOI: 10.1371/journal.pone.0233846.

Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases.

Baek S, Eling T Pharmacol Ther. 2019; 198:46-58.

PMID: 30790643 PMC: 7196666. DOI: 10.1016/j.pharmthera.2019.02.008.

References

Kim J, Chang J, Rhee K, Yoon J, Kwon S, Song K . Cyclooxygenase inhibitors induce apoptosis in sinonasal cancer cells by increased expression of nonsteroidal anti-inflammatory drug-activated gene. Int J Cancer. 2007; 122(8):1765-73. DOI: 10.1002/ijc.23302. View

Boolbol S, Dannenberg A, Chadburn A, Martucci C, Guo X, Ramonetti J . Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res. 1996; 56(11):2556-60. View

Barnes C, Lee M . Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin. Gastroenterology. 1998; 114(5):873-7. DOI: 10.1016/s0016-5085(98)70305-1. View

Hromas R, Hufford M, Sutton J, Xu D, Li Y, Lu L . PLAB, a novel placental bone morphogenetic protein. Biochim Biophys Acta. 1997; 1354(1):40-4. DOI: 10.1016/s0167-4781(97)00122-x. View

Saeki M, Sekine S, Kato S . Human cDNA encoding a novel TGF-beta superfamily protein highly expressed in placenta. J Biochem. 1997; 122(3):622-6. DOI: 10.1093/oxfordjournals.jbchem.a021798. View

Brown D, Ward R, Buckhaults P, Liu T, Romans K, Hawkins N . MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma. Clin Cancer Res. 2003; 9(7):2642-50. View

Zimmers T, Jin X, Hsiao E, McGrath S, Esquela A, Koniaris L . Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury. Shock. 2005; 23(6):543-8. View

Baek S, Okazaki R, Lee S, Martinez J, Kim J, Yamaguchi K . Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia. Gastroenterology. 2006; 131(5):1553-60. DOI: 10.1053/j.gastro.2006.09.015. View

Pang R, Zhou J, Zeng Z, Li X, Chen W, Chen M . Celecoxib induces apoptosis in COX-2 deficient human gastric cancer cells through Akt/GSK3beta/NAG-1 pathway. Cancer Lett. 2007; 251(2):268-77. DOI: 10.1016/j.canlet.2006.11.032. View

10.

Buckhaults P, Rago C, St Croix B, Romans K, Saha S, Zhang L . Secreted and cell surface genes expressed in benign and malignant colorectal tumors. Cancer Res. 2001; 61(19):6996-7001. View

11.

Kim K, Yoon J, Kim J, Baek S, Eling T, Lee W . Cyclooxygenase inhibitors induce apoptosis in oral cavity cancer cells by increased expression of nonsteroidal anti-inflammatory drug-activated gene. Biochem Biophys Res Commun. 2004; 325(4):1298-303. DOI: 10.1016/j.bbrc.2004.10.176. View

12.

Kim K, Baek S, Flake G, Loftin C, Calvo B, Eling T . Expression and regulation of nonsteroidal anti-inflammatory drug-activated gene (NAG-1) in human and mouse tissue. Gastroenterology. 2002; 122(5):1388-98. DOI: 10.1053/gast.2002.32972. View

13.

Antonakopoulos N, Karamanolis D . The role of NSAIDs in colon cancer prevention. Hepatogastroenterology. 2007; 54(78):1694-700. View

14.

Bottone Jr F, Martinez J, Alston-Mills B, Eling T . Gene modulation by Cox-1 and Cox-2 specific inhibitors in human colorectal carcinoma cancer cells. Carcinogenesis. 2003; 25(3):349-57. DOI: 10.1093/carcin/bgh016. View

15.

Sarkar F, Adsule S, Li Y, Padhye S . Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem. 2007; 7(6):599-608. DOI: 10.2174/138955707780859431. View

16.

Baek S, Kim K, Nixon J, Wilson L, Eling T . Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol. 2001; 59(4):901-8. View

17.

Kinzler K, Vogelstein B . Lessons from hereditary colorectal cancer. Cell. 1996; 87(2):159-70. DOI: 10.1016/s0092-8674(00)81333-1. View

18.

Paralkar V, Vail A, Grasser W, Brown T, Xu H, Vukicevic S . Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family. J Biol Chem. 1998; 273(22):13760-7. DOI: 10.1074/jbc.273.22.13760. View

19.

Levy D, Moser A, Dove W, Hamilton S, Vogelstein B, Kinzler K . Sulindac suppresses tumorigenesis in the Min mouse. Carcinogenesis. 1996; 17(8):1757-60. DOI: 10.1093/carcin/17.8.1757. View

20.

Yamada Y, Mori H . Multistep carcinogenesis of the colon in Apc(Min/+) mouse. Cancer Sci. 2006; 98(1):6-10. PMC: 11159231. DOI: 10.1111/j.1349-7006.2006.00348.x. View