Establishment of Prostate Tumor Growth and Metastasis Is Supported by Bone Marrow Cells and Is Mediated by PIP5K1α Lipid Kinase.

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

doi:10.3390/cancers12092719

Abstract

Simple SummaryMetastatic castration-resistant PCa (mCRPC) is a clinically highly lethal disease; the mechanisms underlying the lethal disease remain poorly understood. Furthermore, no effective treatment for cancer metastasis exists. In this study, we have demonstrated that prostate cancer cells required bone marrow-derived cells for their growth, survival and metastasis to the host bone marrow. Our findings have provided new evidence suggesting that cancer cell-specific signals may mediate interactions between prostate cancer cells and bone marrow cells during progression of mCRPC. Therapeutic interventions using a selective inhibitor of lipid kinase PIP5K1α may not only inhibit the growth of primary tumors but may also target the lethal mCRPC within tumor-microenvironment.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.

Highlights

Bone marrow-derived cells, in particular, immune-suppressive myeloid cells, have been shown to accumulate at primary tumor sites following tumor progression, leading to an increased risk for cancer metastasis to distant organs [1,2]
We further showed that the inhibition of PIP5K1α reduced the ability of prostate cancer (PCa) cells to grow in the presence of myeloid cells, suggesting that tumor cells and the tumor microenvironment may be targeted by using selective kinase inhibitors
We have previously reported that PCa cells preferentially home to the bone marrow microenvironment to establish metastatic growth once entering into systemic circulation [22]

Summary

Introduction

Bone marrow-derived cells, in particular, immune-suppressive myeloid cells, have been shown to accumulate at primary tumor sites following tumor progression, leading to an increased risk for cancer metastasis to distant organs [1,2]. Prostate cancer cells may utilize infiltrating bone marrow-derived cells and blood vessels to disseminate and transport to distant organs [6,7,8]. CD11b+ cells were able to promote breast tumor growth and metastasis in mouse models [14]. These findings may shed light for improving current immunotherapy to target the tumor microenvironment. The mechanisms that mediate interactions between immune cells and cancer cells during cancer progression remain poorly understood

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Conclusion