# A novel role of IGFBP7 in the microenvironment of hepatocellular carcinoma

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $486,305

## Abstract

Summary
Evasion from immune surveillance is an important mechanism facilitating tumorigenesis. Identification
of regulators of anti-tumor immunity will help exploit this mechanism to develop effective therapeutic
strategies. Oncogenic insulin-like growth factor (IGF) signaling is suggested to dampen anti-tumor
immune surveillance in hepatocellular carcinoma (HCC). However, there is a gap of knowledge in in-
depth understanding of the underlying mechanism. Insulin-like growth factor binding protein-7
(IGFBP7) inhibits IGF-I signaling and functions as a tumor suppressor in HCC. An Igfbp7 knockout
(Igfbp7-/-) mouse exhibits constitutive activation of IGF signaling and develops spontaneous multi-
organ tumors and markedly accelerated carcinogen-induced HCC compared to +/+ or +/- mice. Igfbp7
expression was significantly higher in stromal cells, such as liver macrophages, versus hepatocytes,
and activated macrophages were increased in Igfbp7-/- mice, suggesting a previously unrecognized
function of Igfbp7 in modulating the tumor microenvironment (TME). A significant inhibition in
expression of immune surveillance regulating genes and a corresponding decrease in antigen
presentation by dendritic cells were observed in Igfbp7-/- mice compared to +/+. Increased
tumorigenesis in Igfbp7-/- mice was associated with decreased tumor infiltration by CD8+ and CD4+ T
cells while Igfbp7-overexpression caused growth inhibition of mouse HCC cells in syngeneic mice,
dependent on the presence of CD8+ and CD4+ T cells. These results suggest that IGFBP7 exhibits
pleiotropic anti-tumor activities and that modulation of an immune response may be an important
component of the tumor suppressor function of IGFBP7, which has not been previously reported. The
long-term objectives of our laboratory are to identify key players regulating HCC and translate this
knowledge into novel and effective targeted therapies. Our recent findings strongly suggest a novel
role of IGFBP7 in regulating the TME and anti-tumor immune response. We hypothesize that
activation of IGF signaling in the absence of IGFBP7 promotes HCC by augmenting cancer cell
proliferation and survival, modulating tumor-microenvironment crosstalk, and impairing tumor immune
surveillance. Therapeutically, administration of IGFBP7 will not only inhibit cancer cell survival, but
also promote immune recognition of tumors, resulting in more effective eradication of tumors and
metastases. We will perform in-depth molecular, biochemical, immunological, and therapeutic studies
using relevant mouse models to establish our hypotheses. Successful completion of the present
studies will help transition IGFBP7 to therapeutic application and thereby help save lives of scores of
HCC patients for whom no effective therapy currently exists.

## Key facts

- **NIH application ID:** 9927609
- **Project number:** 5R01CA240004-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Devanand Sarkar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $486,305
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927609

## Citation

> US National Institutes of Health, RePORTER application 9927609, A novel role of IGFBP7 in the microenvironment of hepatocellular carcinoma (5R01CA240004-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9927609. Licensed CC0.

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