Humanization of the Prostate Microenvironment Reduces Homing of PC3 Prostate Cancer Cells to Human Tissue-Engineered Bone

Jacqui Mcgovern,Pamela Russell,Ferdinand Wagner,Judith Clements,Christoph Lahr,Marietta Landgraf,Boris Holzapfel,Christoph Meinert,Gail Risbridger,Dietmar Hutmacher,Abbas Shafiee,Daniela Loessner,Elizabeth Williams

doi:10.3390/cancers10110438

Abstract

The primary tumor microenvironment is inherently important in prostate cancer (PCa) initiation, growth and metastasis. However, most current PCa animal models are based on the injection of cancer cells into the blood circulation and bypass the first steps of the metastatic cascade, hence failing to investigate the influence of the primary tumor microenvironment on PCa metastasis. Here, we investigated the spontaneous metastasis of PC3 human PCa cells from humanized prostate tissue, containing cancer-associated fibroblasts (CAFs) and prostate lymphatic and blood vessel endothelial cells (BVECs), to humanized tissue-engineered bone constructs (hTEBCs) in NOD-SCID IL2Rγnull (NSG) mice. The hTEBC formed a physiologically mature organ bone which allowed homing of metastatic PCa cells. Humanization of prostate tissue had no significant effect on the tumor burden at the primary site over the 4 weeks following intraprostatic injection, yet reduced the incidence and burden of metastases in the hTEBC. Spontaneous PCa metastases were detected in the lungs and spleen with no significant differences between the humanized and non-humanized prostate groups. A significantly greater metastatic tumor burden was observed in the liver when metastasis occurred from the humanized prostate. Together, our data suggests that the presence of human-derived CAFs and BVECs in the primary PCa microenvironment influences selectively the metastatic and homing behavior of PC3 cells in this model. Our orthotopic and humanized PCa model developed via convergence of cancer research and tissue engineering concepts provides a platform to dissect mechanisms of species-specific PCa bone metastasis and to develop precision medicine strategies.

Highlights

The complications and high mortality of prostate cancer (PCa) are primarily due to the development of distant metastases [1,2]
The formation of mineralized tissue in the humanized tissue-engineered bone constructs (hTEBCs) was confirmed with X-ray imaging 4 weeks after implantation (Figure 1A)
A+C indicated the human origin and survival of the transplanted human pre-osteoblasts (hOBs) in vivo (Figure 1G–I). These results demonstrate that the hTEBC subcutaneously implanted into the murine back flanks generates an organ bone which physiologically recapitulates a localized human bone microenvironment

Summary

Introduction

The complications and high mortality of prostate cancer (PCa) are primarily due to the development of distant metastases [1,2]. It is well established that PCa cells frequently metastasize to the bone [3], the causes for its preferential homing to the bone organ are not fully understood. This may be related to limitations of current preclinical PCa metastasis models which frequently fail to recapitulate tumor formation at the orthotopic site, and overlook the influence of the cellular and extracellular primary tumor microenvironment on PCa growth and metastatic priming, prompting the development of alternative animal models recapitulating the full metastatic cascade. The local tissue microenvironment has gained interest as an important niche for primary and metastatic tumor growth and development [4,5,6]. Human cancer-associated fibroblasts (CAFs), as well as lymphatic and blood vessel endothelial cells (BVECs) have been reported to stimulate the proliferation and metastasis of malignant epithelial cells in vivo [10,11,12,13], indicating the significance of the tumor microenvironment in disease modelling

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