Contrasting effects of IGF binding protein-3 expression in mammary tumor cells and the tumor microenvironment

Tiffany Scully; Carolyn D Scott; Sue M Firth; John E Pintar; Stephen M Twigg; Robert C Baxter

doi:10.1016/j.yexcr.2018.11.006

Contrasting effects of IGF binding protein-3 expression in mammary tumor cells and the tumor microenvironment

Exp Cell Res. 2019 Jan 1;374(1):38-45. doi: 10.1016/j.yexcr.2018.11.006. Epub 2018 Nov 9.

Authors

Tiffany Scully¹, Carolyn D Scott², Sue M Firth³, John E Pintar⁴, Stephen M Twigg⁵, Robert C Baxter⁶

Affiliations

¹ Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia. Electronic address: tiff.scully@gmail.com.
² Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia. Electronic address: carolyn.scott@sydney.edu.au.
³ Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia. Electronic address: sue.firth@sydney.edu.au.
⁴ Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, NJ 08854, USA. Electronic address: pintar@rwjms.rutgers.edu.
⁵ Charles Perkins Centre, Sydney Medical School, University of Sydney, New South Wales 2006, Australia. Electronic address: stephen.twigg@sydney.edu.au.
⁶ Kolling Institute, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia. Electronic address: robert.baxter@sydney.edu.au.

PMID: 30419192
DOI: 10.1016/j.yexcr.2018.11.006

Abstract

IGFBP-3 has both stimulatory and inhibitory effects on cancer progression. The growth of EO771 mammary carcinoma cells as syngeneic tumors in C57BL/6 mice is reduced in Igfbp3-null (BP3KO) mice, suggesting that systemic IGFBP-3 enhances tumor progression. In this study we assessed the growth of EO771 cells expressing human IGFBP-3 in BP3KO mice. Cells expressing hIGFBP-3 showed decreased proliferation in vitro and increased levels of IGF-1 receptor (IGF1R) protein but not mRNA, consistent with sequestration of endogenous IGF by IGFBP-3. The growth rate of these cells was restored by exposure to IGF-1 or analogues with reduced affinity for IGFBP-3 (long Arg³-IGF-1) or IGF1R (Leu²⁴-IGF-1). In EO771 cells implanted orthotopically into mice, hIGFBP-3 expression by the cells inhibited tumor establishment in BP3KO but not wild-type mice. For tumors that successfully established, final weight was not affected significantly by hIGFBP-3 expression. However, final tumor weight was inversely related to intratumoral T cell counts, and sera from BP3KO mice with tumors showed low-titer immunoreactivity against IGFBP-3. The contrasting effects on tumor establishment and progression of IGFBP-3 expressed by mammary carcinoma cells, compared to systemic stromal and circulating IGFBP-3, highlights the complexity of growth regulation by IGFBP-3 in mammary tumors.

Keywords: Breast cancer; IGF-1 analogue; IGFBP-3; Immune response; Tumor establishment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity
Adipose Tissue / pathology
Animals
Antibodies / blood
Antibodies / metabolism
Cell Line, Tumor
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic
Humans
Insulin-Like Growth Factor Binding Protein 3 / metabolism*
Lymphocytes, Tumor-Infiltrating / immunology
Mammary Neoplasms, Animal / blood
Mammary Neoplasms, Animal / genetics
Mammary Neoplasms, Animal / metabolism*
Mammary Neoplasms, Animal / pathology*
Mice, Inbred C57BL
Mice, Knockout
Tumor Microenvironment* / immunology

Substances

Antibodies
Insulin-Like Growth Factor Binding Protein 3