Glioblastoma multiforme: The Octopus in the Brain

Cancer is a life-changing experience. Senator Edward Kennedy has been diagnosed with brain cancer. The ensuing media attention to this horrible disease has touched on a number of fundamental issues. However, the reporting has remained often vague. The vagueness is the inevitable result of the uncertainties involved.

To begin with, uncertainty is an integral part of any cancer. Prognoses of outcome for cancer therapies are probabilistic, diametrically opposed to our craving for definitive answers. We are challenged to beat odds. Yet, we only feel safe, when we know for sure what is going to happen to us. With cancer therapy there can be no assurance of success, only indications from prior experience that the therapy may prolong our lives and hope.

Senator Kennedy's tumor was located in the parietal lobe of the cerebral cortex. This area is large. Nerve cells on its borders process sensory information of mainly one modality. Nerve cells in its interior process multi-modal input, integrating information across multiple senses. The cortical regions that truly fit the idea of the center for a particular function are few. Primary sensory areas may fulfill this requirement best. They receive the most direct input from a particular sense organ and process predominantly information of this sense's modality. For example, a stroke in the primary somatic sensory area at the forward border of the parietal lobe predictably impairs the sense of touch. Therefore, this area may be designated a cortical center for touch. By contrast, injuries in the large swath of parietal cortex stretching backward from the primary somatic sensory area may only lead to subtle loss of sensory function. Attention, speech comprehension and short-term memory may be affected, dependent on the location of the damage. Hence, the uncertainty in the prognosis of the tumor's impact on brain function is rooted in our incomplete understanding of parietal lobe function. More research is needed in this area.

Even less is known about the nature of Senator Kennedy's tumor. Nerve cells and glia represent the most prevalent cell types in brain tissue. Nerve cells multiply at high rate only in the developing brain. In the mature brain, nerve cell proliferation is much reduced and restricted to a small number of regions. In contrast, glia retain the ability to multiply throughout life. The glia in the brain's gray matter essentially consist of astrocytes and microglia.

Astrocytes play vital roles in support of nerve cell function. For example, astrocytes remove the excitatory neurotransmitter glutamate from the space between cells. Neurotransmitters are substances that mediate the transfer of information between nerve cells. Too much glutamate in the extracellular space triggers a program in nerve cells leading to their death (apoptosis). Microglia support the brain's immune response.

After an insult to the brain, astrocytes and microglia increase in number at the site of the injury, owing to cell division and migration. Astrocytes form a glial scar encapsulating the damaged tissue. Microglia are known to incorporate debris of severed nerve cell connections (axons). The glial reaction extends from the site of the injury, following the tracts of severed connections. If the glial reaction progresses normal, the debris is digested and the tissue heals. The glia cease dividing and decrease in number.

At times, however, glia begin to proliferate abnormally without any known reason and the cells do not stop dividing. Aggressive, fast growth of a tumor ensues. Astrocytes develop the most malignant tumors known as glioblastoma multiforme, or GBM for short. Once the tumor reaches a certain size, the blood-brain-barrier is breached. Fluid invades the brain tissue, forming an edema. Nerve cell function is severely impaired, leading to seizures and often hemiparesis. Glia hitherto uninvolved in neoplastic growth react to the injury. The glial reaction possibly recruits abnormal glia and fans out along the disrupted nerve cell connections, infiltrating healthy brain tissue.

At this juncture, the steps to be taken for Senator Kennedy seem straight to the point. The tumor's bulk has been excised. The edema has been addressed. Now, the remaining abnormal astrocytes have to be stopped from dividing. Ionizing radiation will be used to damage the DNA of the cells dividing in the margins of the tumor, arresting the cycle of cell division. Cytostatic chemotherapeutics will be administered to stop astrocytic division in regions outside the focus of radiation. In addition, the growth of blood vessels into cancerous tissue may be slowed with drugs that inhibit angiogenesis (but see addendum, dated Apr. 10, 2009).

I lost my father and two good friends to glioblastoma multiforme and sincerely wish that this regimen will benefit Senator Kennedy in the best possible ways. However, as scientist I know that this vicious disease will only be defeated, once we identify the molecules that signal glial proliferation and devise a method that permits us to specifically inhibit the proliferation of astrocytes.

Addenda

• Most likely, the molecule signaling glial proliferation is epidermal growth factor (EGF) and the EGF tyrosine kinase receptor needs to be inhibited (8/30/08).
• Perhaps, the phosphorylated protein is Annexin/Lipocortin 1 (Melzer and others, 1998) (10/02/08).
• Glioblastoma multiforme is a rapidly growing tumor, showing regional differences from normal brain tissue in its metabolism of sugar as a source of energy. F.M. Santandreu and others (2008) provide a comprehensive description of such metabolic aspects in Cellular Physiology and Biochemistry 22:757-768. Since the tumor cells can store little sugar, the resource has to be delivered constantly with the bloodstream. The fast tumor growth induces growth of blood vessels. Therefore, anti-angiogenic drugs that inhibit vessel growth may help to shrink the tumor (02/18/09).
• Hai Yan and others (2009) report somatic mutations of the mitochondrial enzyme isocitric acid dehydrogenase crucial for sugar metabolism in 70% of astrocytomas and oligodendrogliomas as well as glioblastomas that developed from these tumors (New England Journal of Medicine 360:765-773). The mutations are discussed as potential predispositions for tumorigenesis (02/19/09).
• Microglia reactive to nerve cell injury are shown in my post dated Oct. 17, 2008 (03/04/09).
• To date, there is no compelling evidence that the use of contemporary cell phones causes glioblastoma multiforme. See my post dated Aug. 21, 2008 (03/05/09).
• You may be interested in reckoning with the odds in my post dated Mar. 5, 2009 (03/06/09).
• Erika Check Hayden summarizes the latest insights into the effectiveness and pitfalls of angiogenesis inhibitors in this weeks issue of the journal Nature, vol. 458: 686-687 (04/10/09).
• Using RNA interference (RNAi), Australian scientists developed a method with which the expression of tyrosine kinase receptors can be blocked, making tumor cells more vulnerable to chemotherapeutics and diminishing the tumor cells' ability of developing resistance against the drugs (MacDiarmid and others, 2009). Michael Perry reported on this progress in his post with the title "Scientists kill cancer cells with 'trojan horse'" published online on Reuters yesterday (06/30/09).
• Senator Kennedy passed away yesterday (08/26/09).
• Last Tuesday, Sep. 7, 2009, National Public Radio's Talk of the Nation aired an interview by Neil Conan with the British neurosurgeon Henry Marsh on his charity work in the Ukraine and general aspects of his profession. National Public Television's POV showed a movie on his work that evening. The movie, "The English Surgeon", will available on DVD Nov. 3. Particularly towards the interview's end, Dr. Marsh highlights in striking clarity the importance of finding an experienced neurosurgeon for the successful removal of a glioblastoma (09/10/09).
• A recent clinical study by Sampson and others (2010) reported promising results in the treatment of glioblastoma multiforme (GBM), using vaccines that target epidermal growth factor receptor variant III, or EGFRvIII for short. The receptor is extraordinarily prevalent on the surface of the most-aggressively growing GBM cells, owing to a genetic mutation. Thirty-five patients with GBM were enrolled in the phase II clinical trial; all underwent surgery, radiation therapy and chemotherapy with temozolomide. In addition, 18 were inoculated with vaccines.  Adding vaccines almost doubled median survival time from 15 to 26 months, extending the progression-free period from 6.3 months to 14.2 months. The vaccination eliminated all cancer cells carrying EGFRvIII, except in one patient. Half of the patients showed an immune response. Six developed antibodies specific for the receptor and three showed a T-cell response, supporting the contention that the increased survival may be associated with the immune response. Nine of eleven patients, whose recurring tumors were examined, tested negative for EGFRvIII, indicating that the cells with this mutation had been persistently eradicated. Taken together, the findings suggest that vaccines may prove a promising new avenue of treatment, though not a cure, for glioblastoma muliforme. Celldex Therapeutics and Pfizer developed the currently tested vaccine known as rindopepimut or CDX-110 and PF-04948568, respectively (10/05/10).
• Listen to this interview with Gordon Murray by Robert Siegel broadcast on National Public Radio's All Things Considered today and find words of strength and encouragement from a man with GBM who is making the best of his situation (12/17/10).
• Siddhartha Mukherjee, a hematologist/oncologist at Columbia University, wrote an informative book entitled "The Emperor of All Maladies: A Biography of Cancer" on recent advances in cancer medicine. The author was awarded a Pulitzer Prize for his exploration earlier this month. Note that he specializes in blood cell cancer and the particular experience influences his assessment of the role of stem cells in tumorigenesis and metastasis. Terry Gross interviewed him Nov. 11, 2010, on National Public Radio's Fresh Air in her show with the title "An Oncologist Writes 'A Biography Of Cancer'" (04/22/11).

• 

  Color-coded image of a transaxial FDG PET scan from a GBM patient with a recurrent tumor in the left cortical hemisphere.  High local cerebral metabolic rates for glucose starkly delineate the tumor (low rate - blue; high rate- white; courtesy L. Sokoloff). 

  The functional image above was acquired from a patient with a glioblastoma multiforme in the left cerebral hemisphere. The initial primary tumor and had been surgically removed. The removal was incomplete. When symptoms suggested a recurrence of the tumor, the surgery had altered the anatomy of the cortical hemisphere to such extent that an evaluation of structural brain scans was impossible. However, a new tumor could be localized with positron emission tomography and the [¹⁸F]fluorodeoxyglucose (FDG) method (Di Chiro and others, 1982). This method allows us to image and measure the local glucose consumption of brain tissue. The rate of glucose utilization was highly increased in the core of the new tumor. Under normal physiological conditions, brain cells metabolize glucose to produce adenosine-triphosphate (ATP) in an oxygen-consuming metabolic pathway called aerobic glycolysis. ATP represents a ubiquitous high-energy molecule that cells need to maintain vital functions. Because glia possess only a small capacity of storing glucose and oxygen cannot be stored at all in the brain, the blood supply must continuously deliver both to the brain tissue. An increase in demand stimulates angiogenesis, that is blood vessel growth. However, in fast growing tumors angiogenesis cannot keep pace with demand. Moreover, the activity of certain types of key enzymes for glucose metabolism, known as mitochondria-associated hexokinases I and II, can be increased as much as 200-fold in tumor cells, leading to extremely high rates of aerobic glycolysis (Warburg effect) which compound the local oxygen shortage. Moreover, using tumor genome sequencing Yan and others (2009) identified a mutation that changes arginine 132 in the product of gene IDH1 isocitrate dehydrogenase. Isocitrate dehydrogenase is a key enzyme in the Krebs cycle providing substrates for aerobic glycolysis. This change in amino acid modifies the function of the enzyme such that the enzyme's substrate isocitric acid is turned into a novel product which cannot be used in the Krebs cycle, hampering the efficiency of aerobic glycolysis. More than 70 percent of 445 tested central nervous system tumors were astrocytomas, oligodendrogliomas and glioblastomas that had developed from lower-grade tumors. These rapidly-growing, malignant cancers possessed the mutation. As a consequence, glucose may be metabolized in the malignant tumor's core without the use of oxygen, though this anaerobic glycolysis is much less efficient in generating ATP than aerobic glycolysis. The observations may be taken to suggest the possibility of starving neoplastic astrocytes to death with a diet extremely low in carbohydrates. Alas, cells in other tissues of our body, e.g. muscles, routinely use vast amounts of glucose in anaerobic glycolysis to meet rapidly increasing energy demands while oxygen is in short supply. A no-carb diet is not going to be selective for the tumor and may rather weaken the body's overall resilience. By contrast, avoiding high-fructose corn syrup and sucrose used to sweeten countless foods and beverages may be beneficial, because the fructose in these sugars may stimulate insulin-like growth factors that promote neoplastic growth (see Gary Taubes' article with the title "Is Sugar Toxic?" published online in The New York Times on Apr. 13, 2011) (01/13/2012).
• Dang and others (2009) report that when IDH1 mutations turn arginine 132 into histidine, the gene's changed product isocitric acid dehydrogenase may catalyze the formation of R(-)-2-hydroxyglutarate known to be conducive to tumor growth (02/06/2012).
• The leader of the four-decade effort to develop the deoxyglucose method for the use in tumor imaging (see image above) Dr. Louis Sokoloff presented a historical lecture for the public with the title "Development of the [18F]Fluorodeoxyglucose Method: A Serendipitous Journey From Bench to Bedside" on the endeavor at Brookhaven National Laboratory Oct. 19, 2012, to celebrate the designation of its Chemistry Department by the American Chemical Society as a historical site for its role in this accomplishment (10/29/2012).
• Personal accounts of GBM patients describing their experience with treatment are rare. Two days ago (Sep. 23, 2013), the Washington Post published Fritz Anderson's post with the title "Surgery, radiation and chemo didn’t stop the tumor, but an experimental treatment did" published online. Dr. Anderson, a retired cardiologist, writes about his situation eloquently with great sensitivity and encouragement. After surgery, radiation therapy and chemotherapy his tumor regrew and he decided to participate in an experimental phase I trial of a therapeutic that consists of an altered polio virus (PVS-RIPO) that glioblastoma cells preferentially bind, infecting and destroying the cells. The trial is led by Prof. Matthias Gromeier at Duke University's Preston Robert Tisch Brain Tumor Center. The procedure is invasive, requiring a craniotomy, because the drug must be administered directly to the tumor tissue in one six-hour session. The therapy shrunk the tumor decisively, and Dr. Anderson continues to enjoy life. Four of five treated patients were blessed with success to date (Sep. 25, 2013).

References

• Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden M G, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739-744.
• Di Chiro G, DeLaPaz RL, Brooks RA, Sokoloff L, Kornblith PL, Smith BH, Patronas NJ, Kufta CV, Kessler RM, Johnston GS, Manning RG, Wolf AP (1982) Glucose utilization of cerebral gliomas measured by [18F] fluorodeoxyglucose and positron emission tomography. Neurology 32:1323-1329.
• De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J, Sciot R, Wilms G, Demaerel P, Warmuth-Metz M, Soerensen N, Wolff JE,Wagner S, Kaempgen E, Van Gool SW (2008) Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res 14:3098-3104.
• Check Hayden E (2009) Cutting off cancer's supply lines. Nature 458:686-687.
• MacDiarmid JA, Amaro-Mugridge NB, Madrid-Weiss J, Sedliarou I, Wetzel S, Kochar K, Brahmbhatt VN, Phillips L, Pattison ST, Petti C, Stillman B, Graham RM, Brahmbhatt H (2009) Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nat Biotechnol 27:643-651.
• Melzer P, Savchenko V, McKanna JA (2001) Microglia, astrocytes, and macrophages react differentially to central and peripheral lesions in the developing and mature rat whisker-to-barrel pathway: a study using immunohistochemistry for lipocortin1, phosphotyrosine, s100 beta, and mannose receptors. Exp Neurol 68:63-77.
• Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon II JE, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD (2010) Immunologic Escape After Prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol: doi: 10.1200/JCO.2010.28.6963.
• Santandreu FM, Brell M, Gene AH, Guevara R, Oliver1, Couce ME, Roca P (2008) Differences in mitochondrial function and anti- oxidant systems between regions of human glioma. Cell Physiol Biochem 22:757-768.
• Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765-773.

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