Abstract
While stromal interactions are essential in cancer adaptation to hormonal therapies, the effects of bone stroma and androgen deprivation on cancer progression in bone are poorly understood. Here, we tissue-engineered and validated an in vitro microtissue model of osteoblastic bone metastases, and used it to study the effects of androgen deprivation in this microenvironment. The model was established by culturing primary human osteoprogenitor cells on melt electrowritten polymer scaffolds, leading to a mineralized osteoblast-derived microtissue containing, in a 3D setting, viable osteoblastic cells, osteocytic cells, and appropriate expression of osteoblast/osteocyte-derived mRNA and proteins, and mineral content. Direct co-culture of androgen receptor-dependent/independent cell lines (LNCaP, C4-2B, and PC3) led cancer cells to display functional and molecular features as observed in vivo. Co-cultured cancer cells showed increased affinity to the microtissues, as a function of their bone metastatic potential. Co-cultures led to alkaline phosphatase and collagen-I upregulation and sclerostin downregulation, consistent with the clinical marker profile of osteoblastic bone metastases. LNCaP showed a significant adaptive response under androgen deprivation in the microtissues, with the notable appearance of neuroendocrine transdifferentiation features and increased expression of related markers (dopa decarboxylase, enolase 2). Androgen deprivation affected the biology of the metastatic microenvironment with stronger upregulation of androgen receptor, alkaline phosphatase, and dopa decarboxylase, as seen in the transition towards resistance. The unique microtissues engineered here represent a substantial asset to determine the involvement of the human bone microenvironment in prostate cancer progression and response to a therapeutic context in this microenvironment.
Highlights
Patients with metastatic castrate-resistant prostate cancer (CRPC) present with incurable bone metastases in 90% of cases.[1]
In the clinical management of advanced prostate cancer, radiological, and histological evidence show that all adenocarcinoma prostate cancer types that have metastasized to the bone present with osteoblastic/sclerotic lesions, found in osteoblast-rich areas in the form of woven bone.[3,10]
The clinical co-targeting of osteoclasts, responsible for a fraction of osteolytic metastases, has indicated that osteoclasts only had a secondary role in prostate cancer
Summary
Patients with metastatic castrate-resistant prostate cancer (CRPC) present with incurable bone metastases in 90% of cases.[1]. 75% (Fig. 2a), as expected when osteoblasts transition to osteocytes.[18] Hydroxyapatite (HA) deposition occurred according and appropriate expression of osteoblast and osteocyte-derived to a logarithmic trend (Fig. 2b), with no statistical differences proteins and mineral content This model, viable long-term, can between 10 and 13 weeks osteogenic differentiation, and represent some of the key cellular and microenvironmental throughout the depth of hOBMT (Fig. 2c, d and Fig. S2a). No mineralization was with metastatic prostate cancer cell lines, testing the hypothesis observed on empty control CaP-coated scaffolds cultured in the that the in vitro osteoblastic tumor microenvironment could same conditions (Fig. S2c), in line with osteoblast bio-mineralizareproduce some of the cellular alterations seen in vivo with tion, as seen previously,[19] and as opposed to material-related androgen deprivation
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