Abstract
Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, and bone is the most frequent site of metastasis. The tumor microenvironment (TME) impacts tumor growth and metastasis, yet the role of the TME in PCa metastasis to bone is not fully understood. We used a tissue-engineered xenograft approach in NOD-scid IL2Rγnull (NSG) mice to incorporate two levels of humanization; the primary tumor and TME, and the secondary metastatic bone organ. Bioluminescent imaging, histology, and immunohistochemistry were used to study metastasis of human PC-3 and LNCaP PCa cells from the prostate to tissue-engineered bone. Here we show pre-seeding scaffolds with human osteoblasts increases the human cellular and extracellular matrix content of bone constructs, compared to unseeded scaffolds. The humanized prostate TME showed a trend to decrease metastasis of PC-3 PCa cells to the tissue-engineered bone, but did not affect the metastatic potential of PCa cells to the endogenous murine bones or organs. On the other hand, the humanized TME enhanced LNCaP tumor growth and metastasis to humanized and murine bone. Together this demonstrates the importance of the TME in PCa bone tropism, although further investigations are needed to delineate specific roles of the TME components in this context.
Highlights
Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, and bone is the most frequent site of metastasis
In order to pre-vascularize the human tissueengineered bone construct (hTEBC), a star-shaped polyethylene glycol-heparin hydrogel pre-cultured with human umbilical vein endothelial cells (HUVECs)[23] and a supportive population of human placental mesenchymal stromal cells (MSCs) and human osteoblasts (hOBs) was sandwiched between two medial grade polycaprolactone (mPCL)-calcium phosphate (CaP) scaffolds (Figs. 1b–c and 2a)
Both mPCL-CaP scaffold groups contained the pre-vascularized shaped polyethylene glycol (sPEG)-heparin hydrogels. The rationale for this was to generate an ectopic bone of human origin that contained human-derived bone matrix components and compare this to a bone organ of largely murine origin in order to investigate if preferential metastasis of human PCa cells to humanized bone occurred
Summary
Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, and bone is the most frequent site of metastasis. The humanized prostate TME showed a trend to decrease metastasis of PC-3 PCa cells to the tissue-engineered bone, but did not affect the metastatic potential of PCa cells to the endogenous murine bones or organs. The humanized TME enhanced LNCaP tumor growth and metastasis to humanized and murine bone Together this demonstrates the importance of the TME in PCa bone tropism, further investigations are needed to delineate specific roles of the TME components in this context. We demonstrated in a humanized, orthotopic xenograft model of PCa bone metastasis that the primary tumor microenvironment (TME) had the ability to influence the bone metastatic behavior of PCa cells[7], confirming that the hTEBC is a valuable platform for studying PCa metastasis to human bone. Fibroblasts from the TME like cancerassociated fibroblasts (CAFs) and blood and lymphatic microvascular endothelial cells (MVECs) have been implicated in PCa metastasis, indicating their importance in the prostate TME12–14
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