Journal article
Abstract B203: Heterogeneity in androgen receptor and IL-1beta expression by prostate cancer cells in skeletal metastases
Molecular cancer therapeutics, v 17(1_Supplement), pp B203-B203
01 Jan 2018
Abstract
Abstract Bone metastases are a prevalent complication of advanced prostate cancer (PCa). The current standard of care for advanced PCa patients is androgen deprivation therapy (ADT), which fails within approximately two years and patients progress to castration-resistant prostate cancer (CRPC). CRPC presents with additional metastasis in soft tissues and is incurable. We have found that in PCa patients, bone metastases have heterogeneous androgen receptor (AR) expression, and that cells lacking AR are the only cell type that secretes the cytokine Interleukin-1 beta (IL-1β). Furthermore, preclinical work in our lab has revealed the role for IL-1β in promoting bone colonization by AR+ PCa cells and generation of heterogeneous skeletal metastases. A significant barrier to studying tumor heterogeneity in PCa metastasis has been the lack of an animal model to study the interaction between multiple PCa phenotypes in the bone microenvironment. By engrafting a suspension containing both AR− and AR+ cells directly into the left cardiac ventricle of mice, our lab has developed an in vivo model that allows us to study the progression of both AR− and AR+ cells in skeletal and soft tissue metastases. AR− and AR+ cells were genetically engineered to express two different Luciferase constructs (630 nm Red-shifted Luc and 540 nm Luc2, respectively) thereby allowing the progression of AR− and AR+ cells to be independently tracked and quantified. We used this model in combination with histologic and radiographic analyses to assimilate the pathologic features of our in vivo mixed AR+/AR− metastases to the human clinical scenario. Finally, we used castrated mice to determine whether IL-1β secreting PCa cells could support the growth and survival of IL-1β-/AR+ cells in androgen-deprived conditions. Coinjection of AR− (PC3-ML) and AR+ cells (LNCaP, VCaP, and 22Rv1) leads to increased establishment of soft tissue metastases as compared to injecting AR− cells alone. Unlike the metastases generated by PC3-ML cells alone, which show exclusively osteolytic activity, AR−/AR+ mixed metastases are both osteosclerotic and osteolytic, thereby recapitulating clinical pathology. Finally, preliminary results suggest that coinjection with IL-1β-secreting AR− cells enables the growth of androgen-dependent AR+ cells in castrated mice. This animal model of metastasis heterogeneity recapitulates human pathology and enables further interrogation of the mechanism by which IL-1β supports survival of AR+ cells and the potential role for AR− in evading AR-targeted therapy during CRPC. Citation Format: Asurayya A. Worrede-Mahdi, Alessandro Fatatis. Heterogeneity in androgen receptor and IL-1beta expression by prostate cancer cells in skeletal metastases [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B203.
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Details
- Title
- Abstract B203: Heterogeneity in androgen receptor and IL-1beta expression by prostate cancer cells in skeletal metastases
- Creators
- Asurayya A. Worrede-Mahdi - Drexel UniversityAlessandro Fatatis - Drexel University
- Publication Details
- Molecular cancer therapeutics, v 17(1_Supplement), pp B203-B203
- Publisher
- American Association for Cancer Research (AACR)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000590008800390
- Other Identifier
- 991019168379004721
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- Web of Science research areas
- Oncology