Insulin-like growth factor 2 promotes ovarian cancer growth and resistance to traditional chemotherapy

Ovarian cancer remains the deadliest gynecological cancer worldwide with relatively little advancements in its treatment. Limited knowledge of its molecular origins and the absence of clear symptoms lead to late diagnosis resulting in advanced disease and a poor five-year survival prognosis. Even though initial surgery and chemotherapy treatment reduce pathology, the disease recurs often and frequently develops resistance to standard chemotherapies. The Insulin-like Growth Factor (IGF) signaling axis is involved in several cancers and increased IGF2 expression is suggested to be associated with poor survival in women with ovarian cancer. Here, we sought to determine the role of IGF2 in ovarian cancer growth and chemoresistance.

We observed that Taxol, a standard chemotherapy agent commonly administered to patients with ovarian cancer, induced increased in IGF2 expression in two ovarian cancer cell lines. Similarly, cell lines resistant to multiple microtubule-stabilizing agents also showed increased levels of IGF2 expression. Inhibition of the IGF-signaling pathway with a small-molecule inhibitor or knockdown of IGF2 mRNA sensitized the cells to Taxol, both in cell culture and in xenografts. Immunohistochemistry of ovarian tumor samples showed a significant correlation between high IGF2 expression, advanced stage, tumor grade and decreased disease-free survival. Analysis of mRNA data of The Genome Cancer Atlas of serous ovarian cancer also revealed a significant correlation between increased IGF2 mRNA and reduced progression-free and overall survival.

When IGF2 was constitutively overexpressed in an ovarian cancer cell line, increased xenograft growth was observed as compared to the control-transfected parental cell line. Along with increased growth rate, increased numbers of infiltrating neutrophils were present in the IGF2-overexpressing xenografts. Furthermore, we observed that a human neutrophil-precursor cell line migrated significantly more to the conditioned media of the IGF2-overexpressing HEY cell line in vitro. These findings suggest an important role for IGF2 in tumor growth and responsiveness to standard chemotherapy for ovarian cancer, as well as a potential new target for the precision treatment of certain ovarian tumors.

• Nombre: Jurriaan Brouwer Visser
• Laboratorio: Albert Einstein College of Medicine
• Mención: Ciencias Fisiológicas
• Director Tesis: Ricardo Moreno

Artículos Publicados

1.   Brouwer-Visser J, Huang GS. (2015) IGF2 signaling and regulation in cancer.
 Cytokine Growth Factor Rev. 2015 2015;26(3):371-377 (Review).

2.   Brouwer-Visser J, Lee J, McCullagh K, Cossio MJ, Wang Y, Huang GS. (2014) Insulin-like growth factor 2 silencing restores taxol sensitivity in drug resistant ovarian cancer.
 PLoS One. 9(6):e100165.

3.   Huang GS, Brouwer-Visser J, Ramirez MJ, Kim CH, Hebert TM, Lin J, Arias-Pulido H, Qualls CR, Prossnitz ER, Goldberg GL, Smith HO, Horwitz SB. (2010) Insulin-like growth factor 2 expression modulates Taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer.
 Clin Cancer Res. 16(11):2999-3010.