Host response to cancer cell released signalling molecules is an active area of investigation in our laboratory. We are currently investigating the mechanism(s) associated with cancer-induced pain and cancer-induced depression. We are building on our expertise in bone metastases developed over the last three decades. As an active tissue, bone is constantly remodelling to cope with changing mechanical and functional demands via a coordinated signalling mechanism. Upon invading the bone, cancer cells release a number of factors that interfere with normal bone remodelling. These factors skew remodelling towards the predominantly osteolytic or osteoblastic patterns observed in breast and prostate cancer bone metastases. While most existing research is currently focused on hormone and cytokine mediated pathways of remodelling, our laboratory is also examining glutamatergic signalling. Glutamate is secreted by cancer cells via a well-defined antiporter mechanism that shuttles cystine into the cancer cell for antioxidant synthesis as illustrated in figure to the right. Our laboratory has postulated that glutamatergic signalling may be involved in bone cancer pain, directly activating pain fibres within bone tissue.
We have recently started pursuing a novel link between the unregulated glutamate secretion by cancer cells and the effects on the nervous system that may lead to depression. It is believed that blockade of glutamate signalling in the central nervous system, especially via inhibition of NMDA type glutamate receptors, results in antidepressant effects within hours. This blockade of glutamate receptors results in increased dendritic spine density and therefore increased synaptic activity in the brain. The molecular mechanism implicated in this connection is the mTOR pathway, a ubiquitous protein synthesis and synaptic plasticity signalling pathway. We are currently investigating a number of drugs that inhibit glutamate release from cancer cells and that may also reduce glutamate stimulation in the brain. Such drugs hold enormous clinical potential in dealing with cancer-induced pain and depression in both breast and prostate cancers.
To the left is a visual representation of our hypothesis and model. Prostate and breast cancer cells are used to develop tumours in mouse bone. Glutamate, secreted by the growing tumour through the system xc- antiporter is a key factor contributing to the biological mechanisms of depression. Depression is assessed through behavioural and histological testing. Modulating glutamate signalling at multiple sites will alter the course of prostate cancer-induced depression. Pharmacological agents of interest shown here are sulfasalazine, which inhibits system xc-, and ketamine, which inhibits the NMDA glutamate receptor and may allow an increase in synaptic AMPA glutamate receptor signalling.
We are currently examining various molecular aspects of the oxidative stress caused by cancer cell metabolic activity. Cancer cells derive energy from glucose, fatty acids and glutamine. Functioning at above-normal metabolic rates, cancer cells are addicted to these compounds and thrive in environments rich in them. Of primary importance is the generation of reactive oxygen species (ROS). Upon entering the citric acid cycle (TCA cycle), glutamine and glucose inevitably result in the generation of high levels of ROS due to this predominantly mitochondrial activity. This is a feature commonly displayed by cancer cells, due to their high metabolic rates and high consumption of energy-rich compounds. Cancer cells adapt by altering their antioxidant defence strategy - predominantly via the generation of an antioxidant molecule called glutathione. This adaptation is vital to the survival of the cancer cell, but the cells need to acquire significant amounts of the amino acid cystine from their environment. A side-effect of the import of cystine is the generation of glutamate as an extracellular waste product, and this has implications depending on the tissue location of the cancer cells.
Underlying all of our research themes is the one fundamental factor - oxidative stress. One of the main research strengths of the lab is the investigation of the signalling that occurs via reactive oxygen species (ROS). Cancer cells generate ROS as a consequence of their unique metabolic energy requirements, and one side-effect of this process is the export of excess glutamate. This seemingly innocuous feature connects our ROS studies directly to ongoing work in our lab on cancer pain, cancer depression, and cancer metabolism. Ultimately, we believe that understanding the underlying mechanisms relating to redox homeostasis in both cancer cell and host will allow us to develop therapeutic strategies for cancer symptoms such as pain and depression.