# Paracrine Mechanisms of Prostate Cancer Metastatic Progression

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2020 · —

## Abstract

Prostate cancer is lethal when it metastasizes to the liver. We have identified for the first time that a steatotic
hepatitis (fatty liver) is significantly more receptive to prostate cancer cells than a normal healthy liver. The
Veteran population is predisposed to PCa liver metastasis as they have the multiple risk factors for fatty liver.
In the course of this proposal our objective is to determine the mechanism of this interesting metastatic
phenomena. We have demonstrated that the fatty liver and the primary prostate cancer microenvironment
have multiple lines of similarity, including neuroendocrine differentiation of the epithelia, tenascin C matrix
expression, and endoglin expression in the tumor stromal cells. We have reported that TGF-ß signaling in the
tumor microenvironment in the primary tumor site or the secondary metastatic site mediates paracrine
signaling dictate the expansion and therapeutic resistance of the associated cancer epithelia. The endoglin
receptor is a member of the TGF-ß receptor family that is critical for the switching from the downstream
Smad2/3 to the Smad1/5 signaling. This signaling switch can be the determinant for TGF-ß going from an anti-
tumorigenic role to that of a pro-tumorigenic role. Preliminary data support the induction of fatty acid oxidation
in the primary tumor and hepatocytes downstream of endoglin as a determinant of tumor epithelial expansion
at both primary tumor and metastatic site. In turn, we found that fatty acid metabolism can induce endoglin
expression. We will specifically test the hypothesis that, elevated CD105-fatty acid oxidation axis in the PCa
microenvironment is supportive of its expansion in the primary and liver metastatic site through the following
aims: Aim. 1. Define the role of CD105 and fatty acid oxidation plays in PCa-associated fibroblasts to support
PCa expansion. Aim. 2. Define the role of CD105 and fatty acid oxidation plays in hepatocytes to support PCa
expansion. We will interrogate both stromal and epithelial contributions to the generation and maintenance of a
lethal PCa phenotype in the liver. We will use in vivo tissue recombination and patient derived xenograft
systems to study the interactions of altered cancer-associated fibroblasts and cancer cells. We will for the first
time evaluate endoglin antagonism as a means of limiting PCa liver metastasis. Our studies will leverage
access to human tissues from the well-annotated VA Hospital System. Understanding a mechanism for why
the fatty liver microenvironment supports PCa tumors and determining how the PCa adapts to the metastatic
microenvironment are the goals of this project.

## Key facts

- **NIH application ID:** 9979760
- **Project number:** 5I01BX001040-08
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** Neil A. Bhowmick
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-10-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979760

## Citation

> US National Institutes of Health, RePORTER application 9979760, Paracrine Mechanisms of Prostate Cancer Metastatic Progression (5I01BX001040-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9979760. Licensed CC0.

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