Our Changing Earth

Strategy for the Preferential Elimination of Cancer Cells

The cell surface of mammalian cells is populated with a wide array of proteins that are involved in many aspects of cell-cell communication that is absolutely essential for life. When a normal tissue cell is transformed into a cancerous cell, it often exhibits proteins on the surface that indicate that it has become aberrant – no longer subject to the usual controls that inhibit unrestrained growth.

These “marker” proteins are frequently used to identify cancerous cells and therapeutic strategies are being studied to exploit the presence of these proteins to preferentially kill tumor cells. However, in some types of cancer no unique markers are identifiable.

In order to circumvent this obstacle, Zhiyu Wang from the University of Illinois recently reported on a methodology to positively identify cancer cells that relies on a different approach. Their research strategy can be described in the following way.

 They incubated tumor cultured cells with a class of compounds called sugar azides (structure shown below). The compound DBCO (structure shown below) binds preferentially to sugar azide on the cell surface. In order to ensure that the sugar azide appears only on cancer cells, the researchers modified the sugar azide with protective group that could only be removed with an intracellular tumor-specific enzyme. Once the DBCO-sugar azide complex is on the cell surface, it can be exploited to deliver cancer treating drugs or agents that can used to provide important imaging information.

Azide Sugars

DBCO

This methodology has been successfully employed against colon cancer tumors and metastatic breast cancer in the mouse animal model.

The Metabolic Syndrome

The metabolic syndrome refers to that constellation of risk factors that increase the likelihood of such potentially life-threatening conditions as coronary heart disease (CHD), stroke and diabetes.  It is now estimated that some forty-seven million individuals currently suffer from metabolic syndrome within the United States.  The size of this at-risk population is a cause for concern from a public health perspective.  On account of the fact that this population is growing strongly suggest that there are environmental factors involved and that need to be explored.

The five conditions enumerated below are referred to as metabolic risk factors and they are -

• ·         “A large waistline. This also is called abdominal obesity.  Excess fat in the stomach area is a greater risk factor for heart disease than excess fat in other parts of the body, such as on the hips.
• ·         A high triglyceride level (or you're on medicine to treat high triglycerides). Triglycerides are a type of fat found in the blood.
• ·         A low HDL cholesterol level (or you're on medicine to treat low HDL cholesterol). HDL sometimes is called "good" cholesterol. This is because it helps remove cholesterol from your arteries. A low HDL cholesterol level raises your risk for heart disease.
• ·         High blood pressure (or you're on medicine to treat high blood pressure). Blood pressure is the force of blood pushing against the walls of your arteries as your heart pumps blood. If this pressure rises and stays high over time, it can damage your heart and lead to plaque buildup.
• ·         High fasting blood sugar (or you're on medicine to treat high blood sugar). Mildly high blood sugar may be an early sign of diabetes.”

The projected risk for heart disease, diabetes, and stroke increases with the number of metabolic risk factors presented. The risk of having metabolic syndrome is also closely linked to obesity and a lack of physical activity.

Insulin resistance is a definitive risk factor for the metabolic syndrome and is strongly associated with Type II Diabetes.  Insulin is the small protein hormone produced by specialized cells of the pancreas (Islets of Langerhans).  Insulin (see image below) is produced in response to the presence of elevated glucose in the blood – usually following a meal – and is responsible for regulating glucose levels in the blood.  Insulin resistance refers to that condition in which the body fails to use this hormone properly.

    Structure of Human Insulin

Human Pancreatic Cancer and CD155 Expression

The cell surface transmembrane glycoprotein CD 155 is expressed in many different human tissue cells. This protein has also been shown to be expressed in pancreatic cells in patients suffering from pancreatic cancer. CD 155 is also referred to as a poliovirus receptor (PVR) on account of the fact that it has been implicated in infection with poliovirus in the primate animal model. Current evidence suggests that its function within normal cells is associated with maintaining cohesion between epithelial cells.

S. Nishiwada and his colleagues from the Department of Surgery, Nara Medical University in Kashihara Nara, Japapn have put considerable effort into the study of the role CD 155 expression in human pancreatic cancer within a clinical setting.

In their study of 134 patients with pancreatic cancer, they found that those patients that demonstrated high levels of CD 155 expression also showed a poorer postoperative prognosis than those with low expression of this protein. In addition, they have found an inverse relationship between the expression of CD 155 and the body’s ability to dispatch tumor-infiltrating lymphocytes to the site of the tumor in order to destroy cancerous cells. Furthermore, expression of CD 155 positively correlated with increased growth of the malignancy and angiogenesis – growth of new blood vessels towards the growing tumor. Both of these effects enhances tumor growth. As would be expected, suppression of CD 155 expression, inhibited cell division within pancreatic cancer cells.

Given these important findings, CD 155 may prove to be an important target in pancreatic cancer therapy.

Plasma Membrane Compartments and Cytokine Signaling

The cell (plasma) membrane is a complex array of lipids and proteins that plays an essential role in the communication between the cell and its external environment (see image below).  In complex multi-cellular organisms, individual tissue cells communicate with vast varieties of factors including hormones and cytokines that are found in the tissue fluids that bathe cells and within the circulatory system that delivers nutrients to these cells.

Cytokines are a special class of compounds including interferon (IFN) (see structure below) and interleukins.  These substances are low molecular weight proteins often bound to sugar molecules (glycoproteins) that promote cell to cell communication within the immune system in response to inflammation, infectious agents and trauma.

Interferon

Changiiang You and his colleagues from *the Universitat Osnabruck, Germany, studied in detail the interaction dynamics of the complex array of signaling components and receptors on the plasma membrane especially in regard to IFN.  Interferons augment the immune system response to viral infections and impede the growth of cancerous cells through the regulation of specific genes whose gene products impact cell growth.

The results of their extensive investigation demonstrated that microcompartmentalization plays an essential role in facilitating binding of IFN to its specific receptor on the plasma membrane and the resulting cascade of signaling events that leads to gene expression (see image below).  They found that the maintenance of the integrity of the membrane skeleton (MSK) is of crucial importance.

These finding are of value; because, they help elucidate the complex interactions that are required to insure the successful role of key factors like interferon in proper cell function.

Site Specific Phosphorylation of Tau Inhibits Alzheimer’s in Mice

Alzheimer’s disease impacts many individuals in the latter stages of life.  It is a form of dementia that is very devastating to the individuals affected and their families.  On the molecular level, the disease is indicated by extracellular protein “plaques” that are composed of amyloid-β (Aβ) and an accumulation of so-called, “neurofibrillary tangles” within the neurons (see images below).  These tangles are composed of tau protein.  Amyloids represent aggregates of proteins that are stuck together and pose problems for cellular health and development in tissues.  This is especially important within the central nervous system since communication between neurons is of such vital importance.

The accumulated evidence suggests that it is the combined impact of Aβ and tau that lead to the neuronal dysfunction that is indicated by the severe cognitive deficits exhibited by individual with this disease.  Furthermore, the production of Aβ seems to trigger the subsequent phosphorylation of tau protein that lead to its deposition and ultimately to cognitive deficits.  In mouse animal models, the depletion of tau prevents Aβ toxicity.  It seems that by the time the symptoms are evident, significant cell damage has already occurred.

However, recent studies by Dr. Arne Ittner and his colleagues from the School of Medical Sciences at UNSW Australia have shown that site-specific phosphorylation of tau directed by the neuronal p38 mitogen-activated protein kinase enzyme (p38γ) actually inhibited Aβ toxicity.  Furthermore, the depletion of p38γ worsened cognitive defects and increasing p38γ eliminated these deficits.

 

These results are of importance; for, they demonstrate that phosphorylation of tau may or may not be detrimental depending upon the site(s) on the protein structure that are impacted.

The Impact of Climate Change on Desertification

Climate Change and Desertification - The following is a link to an extensive New York Times article regarding the expansion of the Tengger desert in China and the impact of this change on the affected population -