CXCR4 Expression in Neuroblastic Tumors

Staging System of Neuroblastoma Based on Tumor Spread

Undoubtingly, many of us know of the fatal effects of cancer and that there is currently no cure for it.  Cancer is a group of diseases that are characterized by the uncontrollable division and growth of abnormal cells.  Malignant tumors are formed when cancerous cells invade other areas of the body using the blood or lymph systems.  The spread of cancer throughout the body is termed metastasis and can eventually cause cancer related deaths.  Finding ways to decrease metastasis would yield a decrease in malignancy of tumors.  Although there is not yet a cure for cancer, finding biomarkers can aid in the early diagnosis and treatment of it, which will hopefully increase the survival rates of cancer patients.  

Dr. Alex Carlisle is neuroscientist at Inova Fairfax Hospital and manages the Inova-GMU Neuroscience Translational Research Laboratory partnership.  One of his research focuses is neuroblastoma, a cancer of the sympathetic nervous system.  Neuroblastoma often occurs in infants and young children and accounts for about 15% of pediatric cancer deaths.  As with all illnesses, early diagnosis and treatment is critical.  Children who have neuroblastoma have favorable outcomes when diagnosed at age one or younger.  Detection of cancer in the earlier stages increases the likelihood of it being manageable.  Cancer staging consists of assigning numbers from I to IV to a cancer to label its development.  Stage I cancer is an isolated cancer and increases in severity to stage IV, where the cancer has spread to other areas of the body.  Since neuroblastoma is spontaneous and the characteristics of neuroblastic tumors vary from patient to patient, there is a high need for improved prognostic and therapeutic biomarkers.  Dr. Carlisle’s work has shown that neuroblastoma has a high level of heterogeneity which influences the expression of CXCR4, a chemokine receptor.  CXCR4 may play a crucial role in promoting neuroblastoma metastasis.      

      

CXCR4, expressed on the surface of a variety of cells, is an alpha-chemokine receptor for stromal-derived factor 1 (SDF-1), also called CXCL12.  Chemokines are small glycoprotiens from the cytokine family which direct the movement of cells to their final destinations.  Chemokines are also conserved and have specific ligand-receptor interactions.  This high fidelity between the ligand and receptor may have special functions.

Ligand-Receptor Relationship Between CXCR4 and SDF-1

CXCR4 is known to be a part of HIV infection and is a co-receptor for binding and entry into CD4+ T cells.  However, CXCR4 also plays other biological roles.  It is necessary for normal neuronal development, particularly neural progenitor cell migration during embryogenesis.  Past research has shown that the knockout of CXCR4 results in embryos being unable to reach life and malformation of the dorsal ganglia.  CXCR4 has been clinically associated with the progression of cancer growth, metastasis, and angiogenesis.  Dr. Carlisle’s lab examined the expression of CXCR4 in neuroblastoma cells and its relationship with the progression of the disease.  Human tissue microscopy and CXCR4 staining was used to simultaneously observe the expression of CXCR4 in relation to the progression of neuroblastoma in different patients.  It was found that in ganglioneuroma, benign tumors, CXCR4 expression was low.  Conversely, CXCR4 expression was high in stage IV neuroblastic malignant tumors.  These results suggest that CXCR4 may signal the presence of cancerous cells and their histology.  It is somewhat ironic that although CXCR4 is necessary to the survival of embryos, later on, high expressions of it is linked to the development of neuroblasoma, which may be fatal.  

Biomarkers are Critical for Every Stage in Disease Developement

The aforementioned findings can be applied clinically to determine the development of neuroblastoma and its tumor growth progression.  Now that a link has been established between CXCR4 and neuroblastoma, could CXCR4’s expression levels predict the prognosis of the disease?  More expression of CXCR4 may correlate with higher rates of mortality while low levels of expression indicate higher rates of survival.  This allows the medical field to have more precise examinations of CXCR4 status and the progression of the disease.  Blocking CXCR4 signaling inhibits neuroblastoma growth and provides therapeutic cures.  Plerixafor (AMD3100) is an FDA approved drug currently being used to counteract the effects of increasing levels of CXCR4.  Increasing the concentration of Plerixafor results in a reduction in tumor volume and metastasis.  Although cancer may not be 100% curable, new findings, such as those in Dr. Carlisle’s lab, will provide the groundwork for the development of cures in the future.  How can diagnostic tests be improved to provide closer observations of biomarkers such as CXCR4?  Time is critical to the development of all diseases.  We cannot afford to waste anymore time.      

 

The Importance of Biomarkers in Cancer Treatment

        

References:

http://www.nant.org/pix/inss.jpg

http://www.rsc.org/ej/CS/2012/c2cs35085h/c2cs35085h-f1.gif

http://www.ncbi.nlm.nih.gov/pubmed/23143873

http://www.molecular-cancer.com/content/8/1/126

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002381/

http://www.nant.org/Patients_and_Families/neuroblastoma.php

http://www.ncbi.nlm.nih.gov/pubmed/18847313
https://www.youtube.com/watch?v=lvoCrxLdPno
https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgZCnxOF6fVxUkApyZKyPXhcnZDpxrcD6YIAuODe9jqatmCH6fW8uzkLDgIIVdKoL9ncTTBKsOKFhK4mRZkQe8AdzQhf2JXm19szcRTeP5Wr-J2hpHLuGy-MssZgGCttHLk6SUkKKDyEs0/s1600/Cancer_biomarker_figure.png

Zinc…A Double-Edged Metal

“Never go to excess, but let moderation be your guide.” (Marcus Tullius Cicero)

 

Moderation and balance is the key to living a healthy lifestyle.  Drinking wine is good for your health, however too much can prove to be fatal.  Medicine should always be taken with care as to not overdose and cause more harm to the patient.  Dr. Jane Flinn of the Department of Psychology at George Mason University has done extensive research on the role of metals in behavior and physiology.  More specifically, her research is focused on the roles of zinc (Zn), copper (Cu), and iron (Fe) in learning, memory, Alzheimer’s, and macular degeneration.

 

Have a cold or the flu?  Take a zinc supplement and your recovery rate will accelerate!  But users beware, too much may actually make you more sick.  Zinc is a mineral that is essential to cellular metabolism and immune functions.  Since the human body does not have a specialized storage system for Zn, supplements are available for daily intake.  A lack of Zn could lead to deficits in taste, hindered growth, anemia, and a weakened immune system.  However, just because too little is bad, too much is not necessarily good.  Dr. Flinn’s research suggests that too much Zn can actually harm learning and memory.  Excessive Zn results in a Cu deficiency, which is associated with a reduction in myelination in the brain.  High amounts of Zn have been found in the hippocampus, amygdala, and prefrontal regions of the brain.  Thus, Zn affects spatial memory, a function of the hippocampus, and fear conditioning, a function of the amygdala and prefrontal cortex.  Although the effects of Zn deficiency have been thoroughly researched on, there are few studies that focus on the effects of elevated Zn in the brain. 

Zinc is essential to maintaining health, but too much zinc can have negative effects.

 

In order to investigate the role of Zn in memory and Alzheimer’s, Dr. Flinn manipulated Zn dosages in rats and evaluated their performance in subsequent memory tasks.  The rats were fed Zn-fortified water that also contained Cu and Fe (10 ppm Zn, 0.25 ppm Cu, and 10 ppm Fe).  Controls were given regular lab water.  The rats were then placed in a Morris Water Maze (MWM) and Stationary Atlantis Platform to test their spatial and reference memory.  Three and nine month latencies were measured to assess the effects of elevated levels of Zn in the rats.  After three months, compared to the controls, rats that were fed with Zn-fortified water were significantly slower when learning how to find the submerged platform in the MWM and Stationary Atlantis Platform.  At nine months, the same Zn-fortified rats were much worse at remembering where the platform was located in the tasks and were more anxious during the task.  The results suggested that increased levels of Zn in the rats’ brains impaired their spatial and reference memory.  

In the lab, mice were also raised to carry an APP mutation so that they developed Alzheimer’s-like plaques.  Dietary enhancements of Zn (10 ppm ZnCO3) were administered to the mice and they were then placed in a MWM.  The Zn-fortified mice that had Alzheimer’s-like plaques showed impaired spatial memory.  The elevated level of Zn along with the onset of Alzheimer’s proved to be detrimental to spatial memory performance.

   

Fear conditioning (FC) was also evaluated in relation to elevated levels of Zn.  There are two parts to fear conditioning:  fear acquisition and fear retention.  New learning must take place to learn that a stimulus is no longer fearful and as a result, the fear becomes extinguished.  The mice were placed in boxes for six minutes and a 20-second tone was given at the end of three, four, and five seconds.  During the last two seconds of the tone, a shock was administered to implement delayed conditioning.  The mice were tested on contextual (same box but no tone) and cued (different box with tone but no shock) fear conditioning extinction.  The results showed the Zn enhanced mice froze more and had a slower fear extinction rate, so the levels of Zn and extinction rate were negatively correlated.

Depiction of FC and extinction.  From left to right: Training, Cued FC extinction, and Contextual FC extinction.

 

In both experiments, which evaluated spatial memory and fear learning, the impairments were alleviated by giving the animals small amounts of Cu.  Post-traumatic stress disorder (PTSD) is characterized by the unnecessary retention of fear, which was modeled by the mice mentioned above.  Individuals with PTSD are unable to learn that certain stimuli are no longer fearful and cannot extinguish their fears.  How can the common basis of fear extinction in Zn-fortified animals and patients with PTSD help develop a new treatment for PTSD?  Possibly in the future, Cu supplements can be tweaked and modified to be used as a treatment for PTSD.  Furthermore, supplementation with copper remediated the effects of increased Zn levels in mice that modeled Alzheimer’s disease.  With these findings, the use of dietary supplements with Zn should be monitored in the elderly population, since they are already at risk for Alzheimer’s.  Increasing Zn consumption with the intention of improving health could backfire and have detrimental effects if the dosage is not controlled.  The research discussed above examined the role of Zn in memory, which can be broadly applied to other illnesses as well, such as dementia, anxiety disorders, depression, and mild cognitive impairment.  However, as the field of medical science continues to advance in drug development, we must evaluate whether these drugs are causing more harm than help.      

   

Do we really need all of these supplements?