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Synergistic combination treatment to break cross talk between cancer cells and bone cells to inhibit progression of bone metastasis.

ABSTRACT: Advanced-stage cancers often metastasize to bone, and is the major cause of cancer-related morbidity and mortality. Due to poor biodistribution of intravenously administered anticancer drugs within the bone, chemotherapy is not optimally effective in treating bone metastasis. Additionally, overexpression of receptor activator of nuclear factor ?B ligand (RANKL) in the bone microenvironment drives the vicious, destructive cycle of progression of bone metastasis and bone resorption. We hypothesized that the combination treatment - with docetaxel (TXT), an anticancer drug encapsulated in sustained release biodegradable nanoparticles (TXT-NPs) that are designed to localize in bone marrow, and denosumab monoclonal antibody (DNmb), which binds to RANKL - could be more effective than either treatment alone. We tested our hypothesis in intraosseous prostate cancer (PC-3) cell-induced osteolytic mouse model of bone metastasis with treatments given intravenously. The results demonstrated better efficacy with TXT-NPs than with TXT-CrEL or saline control in inhibiting progression of metastasis and improving survival. TXT-NPs showed ~3-fold higher drug levels in metastasized bone tissue at 1 wk post-administration than TXT-CrEL, thus explaining their efficacy. However, the combination treatment (TXT-NPs + DNmb) given simultaneously was significantly more effective in inhibiting metastatic progression; it caused early tumor regression and improved survival, and caused no body weight loss or tumor relapse, even when the treatment was discontinued, whereas TXT-NPs or DNmb alone treatments showed tumor relapse after an initial regression. Micro-CT analysis of the bone from the combination treatment showed no bone loss and normal bone mineral content, bone density, and bone volume fraction, whereas TXT-NPs or DNmb alone treatments showed bone loss. Confirming the above results, histochemical analysis of the bone from the combination treatment demonstrated normal bone morphology, and osteoblast and osteoclast cell activities. In conclusion, TXT-NPs and DNmb in combination, because of their complementary roles in breaking the cross talk between cancer cells and bone cells, was significantly effective in treating bone metastasis.

SUBMITTER: Vijayaraghavalu S

PROVIDER: S-EPMC6870877 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Synergistic combination treatment to break cross talk between cancer cells and bone cells to inhibit progression of bone metastasis.

Vijayaraghavalu Sivakumar S Gao Yue Y Rahman Mohammed Tanjimur MT Rozic Richard R Sharifi Nima N Midura Ronald J RJ Labhasetwar Vinod V

Biomaterials 20191018

Advanced-stage cancers often metastasize to bone, and is the major cause of cancer-related morbidity and mortality. Due to poor biodistribution of intravenously administered anticancer drugs within the bone, chemotherapy is not optimally effective in treating bone metastasis. Additionally, overexpression of receptor activator of nuclear factor κB ligand (RANKL) in the bone microenvironment drives the vicious, destructive cycle of progression of bone metastasis and bone resorption. We hypothesize ...[more]

PMID: 31654872

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Project description:BackgroundBone metastasis is the leading cause of death in patients with prostate cancer (PCa) and currently has no effective treatment. Disseminated tumor cells in bone marrow often obtain new characteristics to cause therapy resistance and tumor recurrence. Thus, understanding the status of disseminated prostate cancer cells in bone marrow is crucial for developing a new treatment.MethodsWe analyzed the transcriptome of disseminated tumor cells from a single cell RNA-sequencing data of PCa bone metastases. We built a bone metastasis model through caudal artery injection of tumor cells, and sorted the tumor hybrid cells by flow cytometry. We performed multi-omics analysis, including transcriptomic, proteomic and phosphoproteomic analysis, to compare the difference between the tumor hybrid cells and parental cells. In vivo experiments were performed to analyze the tumor growth rate, metastatic and tumorigenic potential, drug and radiation sensitivity in hybrid cells. Single cell RNA-sequencing and CyTOF were performed to analyze the impact of hybrid cells on tumor microenvironment.ResultsHere, we identified a unique cluster of cancer cells in PCa bone metastases, which expressed myeloid cell markers and showed a significant change in pathways related to immune regulation and tumor progression. We found that cell fusion between disseminated tumor cells and bone marrow cells can be source of these myeloid-like tumor cells. Multi-omics showed the pathways related to cell adhesion and proliferation, such as focal adhesion, tight junction, DNA replication, and cell cycle, were most significantly changed in these hybrid cells. In vivo experiment showed hybrid cells had a significantly increased proliferative rate, and metastatic potential. Single cell RNA-sequencing and CyTOF showed tumor-associated neutrophils/monocytes/macrophages were highly enriched in hybrid cells-induced tumor microenvironment with a higher immunosuppressive capacity. Otherwise, the hybrid cells showed an enhanced EMT phenotype with higher tumorigenicity, and were resistant to docetaxel and ferroptosis, but sensitive to radiotherapy.ConclusionTaken together, our data demonstrate that spontaneous cell fusion in bone marrow can generate myeloid-like tumor hybrid cells that promote the progression of bone metastasis, and these unique population of disseminated tumor cells can provide a potential therapeutic target for PCa bone metastasis.

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Synergistic combination treatment to break cross talk between cancer cells and bone cells to inhibit progression of bone metastasis.

Publications

Synergistic combination treatment to break cross talk between cancer cells and bone cells to inhibit progression of bone metastasis.

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