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Dissertation
Osteoblasts modulate calcium signaling in bone metastatic breast and prostate cancer cells
Doctor of Philosophy (Ph.D.), Drexel University
May 2010
DOI:
https://doi.org/10.17918/00000641
Abstract
Skeletal metastases are a significant cause of morbidity in patients with breast and prostate cancers, causing complications such as pathological fractures, bone pain and spinal cord compression. While current treatment options in the majority of patients alleviate pain and reduce the risk of skeletal complications, they do not improve survival. Following arrival in the bone, disseminated cancer cells must acquire the ability to adapt and survive within the intricate network of signaling-stromal interactions existing in the microenvironment. Metastases in bone cause perturbations of normal physiological remodeling processes, inducing both bone resorption and formation, resulting in excess release of bone derived minerals such as calcium. The effects induced on cancer cells by surrounding bone stroma and high extracellular calcium may modulate their subsequent physiological responses. Intracellular calcium is a second messenger which regulates numerous cellular processes-in all eukaryotic cells. Calcium signals exhibit numerous temporal and spatial patterns that can ultimately determine cellular fate. For example, high sustained levels of intracellular calcium often results in necrotic or apoptotic cell death. This dissertation employs in vitro and in vivo methods, including fluorescence and real-time digital imaging of live single cells, to investigate the role exerted by the bone microenvironment on properties of intracellular calcium signaling in human breast and prostate cancer cells. Bone-metastatic cells co-cultured with normal human osteoblasts, displayed a significant increase in the small fraction of cells which constitutively and cyclically responded to agonist stimulation with a moderate elevation of intracellular calcium. Notably, non bone-metastatic cells responded to agonists with uniform high cytosolic increases and were not affected by osteoblasts. The reduced calcium elevation observed in bone-metastatic cells likely results from diminished entry of this ion from the extracellular space. Interestingly, cancer cells recovered from experimental skeletal metastases induced in mice showed agonist-induced calcium responses identical to cells co-cultured with osteoblasts. However, cells disseminated to soft-tissues did not, emphasizing the involvement of the bone microenvironment in the phenomenon. Finally, silencing the CAV3. I subtype of T-type calcium channels in non-bone metastatic prostate cancer cells resulted in a marked attenuation of extracellular calcium influx and their ability to form skeletal tumors in our mouse model of metastases. In conclusion, these observations strongly indicate that the ability of selected malignant cells to maintain low cytosolic Ca²⁺ may facilitate their progression into skeletal metastases. Identification of the molecular entities involved opens a new avenue for therapeutic intervention to counteract the adaptation of disseminated cancer cells to the bone microenvironment.
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Details
- Title
- Osteoblasts modulate calcium signaling in bone metastatic breast and prostate cancer cells
- Creators
- Julia D'Ambrosio
- Contributors
- Alessandro Fatatis (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvii, 152 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991014970183204721