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Establishment of prostate tumor growth and metastasis is supported by bone marrow cells and is mediated by pip5k1α lipid kinase

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  • Richard Karlsson
  • Per Larsson
  • Regina Miftakhova
  • Azharuddin Sajid Syed Khaja
  • Martuza Sarwar
  • Julius Semenas
  • Sa Chen
  • Andreas Hedblom
  • Tianyan Wang
  • Kristina Ekström-Holka
  • Athanasios Simoulis
  • Anjani Kumar
  • Ødum, Niels
  • Thomas Grundström
  • Jenny L. Persson

Cancer cells facilitate growth and metastasis by using multiple signals from the cancer-associated microenvironment. However, it remains poorly understood whether prostate cancer (PCa) cells may recruit and utilize bone marrow cells for their growth and survival. Furthermore, the regulatory mechanisms underlying interactions between PCa cells and bone marrow cells are obscure. In this study, we isolated bone marrow cells that mainly constituted populations that were positive for CD11b and Gr1 antigens from xenograft PC-3 tumor tissues from athymic nu/nu mice. We found that the tumor-infiltrated cells alone were unable to form tumor spheroids, even with increased amounts and time. By contrast, the tumor-infiltrated cells together with PCa cells formed large numbers of tumor spheroids compared with PCa cells alone. We further utilized xenograft athymic nu/nu mice bearing bone metastatic lesions. We demonstrated that PCa cells were unable to survive and give rise to colony-forming units (CFUs) in media that were used for hematopoietic cell colony-formation unit (CFU) assays. By contrast, PC-3M cells survived when bone marrow cells were present and gave rise to CFUs. Our results showed that PCa cells required bone marrow cells to support their growth and survival and establish bone metastasis in the host environment. We showed that PCa cells that were treated with either siRNA for PIP5K1α or its specific inhibitor, ISA-2011B, were unable to survive and produce tumor spheroids, together with bone marrow cells. Given that the elevated expression of PIP5K1α was specific for PCa cells and was associated with the induced expression of VEGF receptor 2 in PCa cells, our findings suggest that cancer cells may utilize PIP5K1α-mediated receptor signaling to recruit growth factors and ligands from the bone marrow-derived cells. Taken together, our study suggests a new mechanism that enables PCa cells to gain proliferative and invasive advantages within their associated host microenvironment. Therapeutic interventions using PIP5K1α inhibitors may not only inhibit tumor invasion and metastasis but also enhance the host immune system.

OriginalsprogEngelsk
Artikelnummer2719
TidsskriftCancers
Vol/bind12
Udgave nummer9
Sider (fra-til)1-19
Antal sider19
ISSN2072-6694
DOI
StatusUdgivet - 2020

ID: 249772792