In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer

Abstract

While androgen-targeted therapies are routinely used in advanced prostate cancer (PCa), their effect is poorly understood in treating bone metastatic lesions and ultimately results in the development of metastatic castrate resistant prostate cancer (mCRPC). Here, we used an all-human microtissue-engineered model of mineralized metastatic tissue combining human osteoprogenitor cells, 3D printing and prostate cancer cells, to assess the effects of the antiandrogens, bicalutamide, and enzalutamide in this microenvironment. We demonstrate that cancer/bone stroma interactions and antiandrogens drive cancer progression in a mineralized microenvironment. Probing the bone microenvironment with enzalutamide led to stronger cancer cell adaptive responses and osteomimicry than bicalutamide. Enzalutamide presented with better treatment response, in line with enzalutamide delaying time to bone-related events and enzalutamide extending survival in mCRPC. The all-human microtissue-engineered model of mineralized metastatic tissue presented here represents a substantial advance to dissect the role of the bone tumor microenvironment and responses to therapies for mCPRC.

A novel mechanobiological model of bone metastasis reveals that mechanical stimulation inhibits the pro-osteoclastogenic effects of breast cancer cells

“…These studies showed the specificity of breast and prostate CCs towards metastasizing to bone as well as established 3D humanized in vitro models of bone to study differences in tumor colonization and proliferation between healthy and osteoporotic condition. A recent experimental model used bioprinted calcium phosphate coated polycaprolactone scaffolds cellularized with human osteoprogenitor cells, which were then seeded with human prostate CCs 34 to study response to androgen-targeted therapy. They reported that cancer/bone stroma interactions and anti-androgens drive cancer progression in a mineralized microenvironment.…”

“…More recently, three-dimensional (3D) in vitro tumor models have been developed to study the invasion of breast cancer cells into bone samples from patients undergoing total hip replacement 32,33 . A recent experimental model used bioprinted calcium phosphate coated polycaprolactone scaffolds cellularized with human osteoprogenitor cells, which were then seeded with human prostate cancer cells 34 to study response to androgen-targeted therapy. They reported that cancer/bone stroma interactions and anti-androgens drive cancer progression in a mineralized microenvironment.…”

Sustained release of alpha‐methylacyl‐CoA racemase (AMACR) antibody‐conjugated and free doxorubicin from silica nanoparticles for prostate cancer cell growth inhibition

“…It was also the fifth major cause of cancer death in 2020, with about 1.4 million new cases and 375,000 deaths worldwide. Unfortunately, the pathogenesis of PC is not well understood, 3 although age, family history of PC patients, and certain genetic mutations (e.g., BRCA1 and BRCA2) are known risk factors 1 . The highest incidence rates of PC are found in men of African descent that are also known to be highly susceptible to high risks of PC 1–3 .…”

“…Unfortunately, the pathogenesis of PC is not well understood, 3 although age, family history of PC patients, and certain genetic mutations (e.g., BRCA1 and BRCA2) are known risk factors 1 . The highest incidence rates of PC are found in men of African descent that are also known to be highly susceptible to high risks of PC 1–3 . However, PC is most likely to develop in men during the later stages of life 1–3 .…”

“…1 The highest incidence rates of PC are found in men of African descent that are also known to be highly susceptible to high risks of PC. [1][2][3] However, PC is most likely to develop in men during the later stages of life. [1][2][3] Commonly used PC treatment methods include minimally invasive ablation therapies [4][5][6] ; radiation therapy 7 ; surgery, such as radical prostatectomy 7,8 ; hormone therapy 9 ; cryotherapy, 10 and chemotherapy.…”