Understanding the Employment of the Brain Microenvironment by Metastatic Tumor Cells
Brain metastases occur when cancer cells from a primary tumor travel to a distant organ site to form another tumor. Due to the lack of effective treatments and a general deficiency in research into the causes of metastases, the prognosis for patients with brain metastases is poor. One project under investigation is the advantage tumors cells take of the brain microenvironment to improve their ability to survive and establish a metastatic tumor. The brain microenvironment includes the neurotransmitters, neurotrophins, and their associated receptors that can be employed by the metastatic tumor cells. Normally, neurotransmitters and neurotrophins are factors released by brain cells to maintain a balanced brain environment. In our current research in breast cancer brain metastasis, we have found that breast cancer cells that metastasize to the brain express brain-like characteristics, such as GABA and Trk receptors, which were initially thought to be expressed solely on brain cells. We are currently investigating how the breast tumor cells use their own GABA and Trk receptors to increase their metastatic potential in the brain by utilizing the neurotransmitters and neurotrophins provided by the surrounding brain cells.
In addition to the advantage tumor cells take of the brain microenvironment through factors released by brain cells, tumor cells can manipulate the surrounding brain cells, including neural progenitor cells, surrounding the tumor. We have researched the impact of a bone-morphogenic protein on the neural stem cells surrounding the tumor. Our studies show a bidirectional relationship between the tumor cells and the neural stem cells through the release and binding of bone-morphogenic proteins. By understanding the mechanisms metastatic cells use to exploit and manipulate the surrounding brain microenvironment to establish a metastatic tumor, we can increase chances to potentially prevent the formation of brain metastases.
Improving Treatment Options for Brain Tumors and Metastases
Due to the brain’s extreme sensitivity and vital function, patients with primary or metastatic brain cancer have poor prognoses. Current treatments are limited and often futile, since most drugs cannot cross the blood-brain-barrier and greatly diminish patient’s quality of life by killing healthy brain. Therefore, further investigation of BBB permeable drugs with a high affinity to only kill tumor cells is vital. Through collaborations with scientists in the Department of Molecular Medicine, we are investigating the efficacy of a novel chemotherapeutic drug that exploits the tumor cell’s unique metabolism to treat glioblastomas and metastatic brain cancers.
There are two metabolic pathways that cells utilize to multiply and grow: aerobic and anaerobic respiration. Healthy cells rely on aerobic respiration due to its efficient use of nutrients and lack of toxic by-products. But, aerobic respiration requires access to oxygen and thus under oxygen-deficient conditions, cells will rely on anaerobic respiration. Cancer cells are shown to heavily rely on anaerobic respiration even with little available oxygen. One focus in this lab is to utilize this knowledge to develop a treatment which specifically kills the cancer cells and not the healthy brain cells by removing the reliance on anaerobic respiration.
The tumor cell makes an enzyme called glyoxalase I (Glo1) which detoxifies methylglyoxal, a toxic substance produced by the anaerobic pathway. A substance called “GloX1” (discovered at City of Hope) eliminates the ability of Glo1 to detoxify methylglyoxal, thus causing an accumulation of the toxin leading to cell death. By determining the concentration of GloX1 necessary to kill tumor cells with minimal effects on normal brain cells, GloX1 could potentially eliminate the cancer while not harming the healthy brain cells. In addition to preferentially targeting tumor cells, GloX1 shows great promise for future clinical trials since it has been shown to cross the blood-brain-barrier. Therefore, if our lab shows that GloX1 is effective at killing primary or metastatic brain cancer, it would be more implementable in a clinical trial since only simple systemic administration of the drug is required.