Functions of Tenascin-C and Integrin alpha9beta1 in Mediating Prostate Cancer Bone Metastasis
Abstract
Scientific Rationale: We have shown that prostate cancer cells selectively form colonies at sites of trabecular bone in patient metastatic prostate cancer bone samples. This study showed that colonies of prostate cancer cells were localized on trabecular bone surfaces that were high for the protein tenascin-C. Little is understood about the mechanisms that mediate the selective metastasis of human prostate cancer cells to trabecular bone. Tenascin-C is normally deposited at bone surfaces undergoing repair or at sites of inflammation. To better understand this process, we developed several in vitro model systems that mimic the high tenascin-C bone surface. This includes a novel three-dimensional bone model made with adult human mesenchymal stem cells induced to differentiate to bone. In addition, we have developed a bovine trabecular bone cube (TBC) model that is coated with human tenascin-C. These models also show preferential attachment and growth in regions high in tenascin-C. Screening has shown that integrin alpha9-beta1 on prostate cancer cells mediates the adhesion of prostate cancer cells to tenascin-C positive bone surfaces. We propose that alpha9-beta1 is a key component of prostate cancer cell interaction with reactive endosteum and this integrin mediates cell seeding and colony formation on trabecular bone surfaces. However, integrin alpha9-beta1 is understudied in prostate cancer. This project proposes straightforward experiments to test the hypotheses directly. The proposal is based on two novel model systems, the human-human organoid model and the trabecular bone cube (TBC) model. Both of these can be used for in vitro and in vivo studies to address prostate cancer cell interactions with bone surfaces. Applicability of the Research: We anticipate generating data that will help us to better understand the fundamental mechanisms that mediate interactions of prostate cancer cells with the bone surface. This will include understanding the upstream role of integrin alpha9-beta1 and potential downstream mediators. Our study is designed to pinpoint the signaling mechanisms mediated by integrin alpha9-beta1 in prostate cancer cells and to determine which of these are responsible for adhesion, phenotype changes, and proliferation of prostate cancer cells on bone surfaces. These data will help in the development of novel therapeutic approaches to inhibit prostate cancer seeding, colony formation, and/or growth on trabecular bone. Contributions of the Research to Advancing Prostate Cancer Research: This project will impact the Prostate Cancer Research Program (PCRP) focus area of understanding the tumor microenvironment as it address the biology of prostate cancer cells interaction with the microenvironment of reactive endosteum in metastatic tumors. We believe that seeding onto a tenascin-C high osteoblastic reactive endosteum by prostate cancer cells is a key stem in colony initiation, colony progression to metastatic disease, which is therapeutic-resistant in many patients. We submit that an understanding of the mechanisms of alpha9-beta1 action in metastasis is important to the PCRP challenge areas of "developing effective treatments and address mechanisms of resistance for men with high-risk or metastatic prostate cancer." Finally, we hope that the understanding the role of alpha9-beta1 will help in the development of novel therapeutics. Such therapeutics would target the tumor cells interaction with the tumor microenvironment that promotes cancer cell interaction with the bone surface. The proposed studies will determine whether alpha9-beta1 integrin is responsible for preferential metastasis to bone, an important advancement.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610523
Entities
People
- David R. Rowley
Organizations
- Baylor College of Medicine
- United States Army