Glutamate intercellular communication in bone metastasis
Theses
Overview
Overview
abstract
Bone is the most frequent site for metastasis of breast and prostate cancers, often resulting in pathologic changes in bone metabolism and severe pain. A number of factors released by tumour cells have been shown to interfere with the fine balance that exists between bone resorption and formation in normal bone. The amino acid and neurotransmitter glutamate is known to be critical to bone homeostasis, and we have found that cancer cell lines used to generate bone tumours in animal models secrete significant amounts of glutamate in vitro. Furthermore, we subsequently identified the molecular transport mechanism responsible for this glutamate release in vitro and in vivo and demonstrated its pharmacological inhibition. To support the validity of the concept of tumour-derived glutamate leading to functional effects in bone, evidence was presented to show that glutamate or modulation of its receptors and transporters can have significant impact on the differentiation and functions of both osteoclasts and osteoblasts. We suggest that glutamate release is a plausible mechanism to account for many of the pathological changes in bone metastasis, primarily since bone is so highly sensitive to glutamatergic disruption. Considering the pathological effects of bone metastasis as a communication problem represents a novel approach to the understanding of cancer cell biology and may lead to practical targets for therapeutic intervention in bone metastasis and chronic bone cancer pain. ISBN: 978-0-494-65918-2
