Project 4

Role of Bone Microenvironment in Tax-Induced Malignancies

Principal Investigator: Katherine Weilbaecher, MD, Washington University
Co-Principal Investigator: Thomas Rosol, DVM, PhD, The Ohio State University

Most humans (>80%) that develop Adult T-cell Lymphoma/Leukemia (ATL) due to HTLV-1 infection develop humoral hypercalcemia of malignancy (HHM), which is an important cause of morbidity and mortality in affected patients. The HTLV-1 viral oncoprotein, Tax, has been demonstrated to play a critical role in the pathogenesis of ATL. During the past 4 years, we have found that Tax-induced malignancies produce alterations in the tumor microenvironment that enhance tumor growth, bone destruction and severity of disease. Tax induces the expression of several bone-trophic and inflammatory factors that recruit host cells that alter the tumor microenvironment such as: osteoclasts (OCs), osteoblasts (OB), endothelial cells, neutrophils and tumor-infiltrating lymphocytes. Because Tax-expressing cells interact with a variety of host cell types, we have developed and utilized animal models of Tax-induced malignancies to study the effects of Tax on these cells. We have identified parathyroid hormone-related protein (PTHrP), interferon gamma (IFNγ), Receptor Activator of NFκB ligand (RANKL), RANK (receptor for RANKL), and macrophage inflammatory protein-1ά (MIP-1ά, as important molecules in the tumor and its microenvironment.

We hypothesize that RANKL/RANK signaling is the critical common pathway by which Tax-induced factors alter the bone microenvironment to cause the bone destruction and hypercalcemia characteristic of ATLL. In collaboration with Project 5, the animal core C, and the biostatistics core A, we have developed three Tax-induced malignancy models that induce osteolytic disease (enhanced osteoclastic resorption-in granzymeB-Tax (Tax+) transgenic lymphoma/leukemia hypercalcemia-prone mice), osteoblastic disease (enhanced OB bone formation- in the Tax+Arf-/- mouse model of malignant osteosarcoma), and mixed osteolytic/osteoblastic disease (TGN; a Tax+ carcinoma). Project 3 has found that the tumor suppressor arf is a target gene of RNA helicase A (RHA) and in collaboration with Project 3, we will further dissect the roles of RHA and ARF in osteosarcoma and Tax-induced lymphoma.

There are three specific aims to this proposal: 1) Characterize the mechanism(s) by which Tax-induced tumor cells induce RANKL production and modulate of RANK signaling in osteolytic bone disease and HHM., 2) Define the molecular mechanisms by which tumor cells from Tax-induced malignancies alter normal osteoblast biology, and 3) Define the molecular pathogenesis of a novel animal model of human osteosarcoma in Tax+Arf-/- mice.