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Targeting the αVβ3/ngr2 Pathway in Neuroendocrine Prostate Cancer

Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVβ3 integrin is over-expressed in neuroendocrine prostate cancer.

We now show that LM609, a monoclonal antibody that specifically targets the human αVβ3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo. Our group has recently identified a novel αVβ3 integrin binding partner, NgR2, responsible for regulating the expression of neuroendocrine markers and for inducing neuroendocrine differentiation in prostate cancer cells. Through in vitro functional assays, we here demonstrate that NgR2 is crucial in promoting cell adhesion to αVβ3 ligands. Moreover, we describe for the first time co-fractionation of αVβ3 integrin and NgR2 in small extracellular vesicles derived from metastatic prostate cancer patients' plasma. These prostate cancer patient-derived small extracellular vesicles have a functional impact on human monocytes, increasing their adhesion to fibronectin. These monocytes, upon incubation with small extracellular vesicles, do not show an associated change in conventional polarization marker expression and appear to be in an early stage that may be defined as "adhesion competent". Overall, these findings allow us to better understand integrin-directed signaling and cell-cell communication during cancer progression. Furthermore, our results pave the way for new diagnostic and therapeutic perspectives for patients affected by neuroendocrine prostate cancer.
Anna Testa,1 Fabio Quaglia,1 Nicole M Naranjo,1 Cecilia E Verrillo,1 Christopher D Shields,1 Stephen Lin,1 Maxwell W Pickles,1 Drini F Hamza,1 Tami Von Schalscha,2 David A Cheresh,2 Benjamin Leiby,3 Qin Liu,4 Jianyi Ding,4 William K Kelly,5 D Craig Hooper,1 Eva Corey,6 Edward F Plow,7 Dario C Altieri,8 Lucia R Languino1

  1. Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
  2. Department of Pathology, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, United States of America.
  3. Division of Biostatistics, Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
  4. Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
  5. Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
  6. Department of Urology, University of Washington, Seattle, Washington, United States of America.
  7. Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
  8. Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
Source: Testa A et al. (Nov 11, 2023) Targeting the αvβ3/NGR2 pathway in neuroendocrine prostate cancer, Matrix biology : journal of the International Society for Matrix Biology.