As an ER doc, I have a limited role in the realm of cancer. My usual practice involves either managing complications of cancer therapy, or being faced with the undesirable job of explaining to a very nice person that she now has cancer( ER pearl: niceness varies directly in proportion to cancer risk). I do not conduct research on the metabolic, genetic and molecular aspects of these diverse diseases, and I have great respect for those that do. Also somewhat inconsistent with my snapshot, continuity-lacking practice of emergency medicine is my obsession with diet and exercise. But when the low-carb diet proponents started making claims about cancer, I couldn’ t resist diving in.
One thing I was pretty sure I knew about cancer was that it has a genetic basis. Radiation, a virus, chimney soot, or sporadic bad luck causes a mutation in the double helix and a monoclonal cell line recklessly proliferates. This Somatic Mutation Theory( SMT) of cancer receives most of the attention, and of course funding. Many of you have heard of The Cancer Genome Atlas( TCGA). Churning out petabytes of data, more bytes than stars in Milky Way, the TCGA’ s impressive description of cancer genetics has left scientists somewhat confused. Instead of a few mutations causing most cancers, researchers found some cancers with no apparent mutations, and several others with no consistent patterns of DNA damage. I was surprised especially by the tumor heterogeneity. Cell lines differ not just between people( intertumoral), but within individuals( intermetastatic), and even within single tumors( intratumoral). Were the SMT and TCGA too big to fail?
The metabolic story of cancer begins in the 1920s with Otto Heinrich Warburg, MD, PhD. It is not surprising this Jewish German Nobel-winning scientist was indomitable and stubborn. Arguing with his peers until he died, his Warburg Effect describes the“ one prime cause of cancer … replacement of respiration of oxygen in normal body cells with fermentation of sugar.”
Okay now take a few deep breaths. We must travel back to biochemistry class. Glucose provides energy in the form of ATP. First glycolysis turns glucose into pyruvate, making 2 ATP. If oxygen is present, pyruvate then moves into mitochondria for the Kreb’ s cycle and electron transport chain( ETC) to make 34 more ATP. But if you are holding your breath while running from a tiger, your pyruvate will be converted to lactic acid( no Kreb’ s or ETC) and your legs burn from the lactate. Most cancer cell types act like they are in an anaerobic environment. They can have rates of glycolysis up to 200x the rate of normal cells. They essentially ignore the efficient mitochondria sitting there waiting for pyruvate( maybe because
the mitochondria are damaged). This might be because cancer cells desperately want to avoid apoptosis, a process initiated by mitochondria. It might be because the cancer cell actually thinks it is in a low oxygen environment( Warburg exposed normal cells to hypoxia to turn them into cancer cells).
So now you should be picturing highly metabolically active, sugar-crazed cancer cells. Want to see where they are in the body? Tag a glucose molecule with positron-emitting radionucleotide fluorine-18, and watch all of the areas with these cells light up on a PET scan.
Another reason the cancer cell might be so obsessed with glycolysis relates to the first step of glycolysis, conversion of glucose to glucose-6-phosphate( G6P) by hexokinase. Most cancer cells have a rogue hexokinase, hexokinase II / B. Unlike normal hexokinase, Hexokinase II / B is not feedback inhibited by copious G6P piling up in the cytoplasm- it just keeps making more. Hexokinase II / B also binds the voltage dependent anion channel( VDAC), which prevents cytochrome c release( and therefore prevents apoptosis). Another enzyme recently implicated is tumor M2-PK, a pyruvate kinase that is only active in normal cells if they must divide rapidly( healing wound, hematopoiesis, etc.). Tumor M2-PK enables cancer cells to consume glucose at a rapid rate. If you want to know more, check the references on the Wikipedia pages for Warburg Effect or Warburg Hypothesis, but be ready for irresistibly deep internet rabbit holes.
Due to the high rate of glycolysis, the cancer cell produces gobs of pyruvate, which get converted to lactate. Cancer cells upregulate monocarboxylate transporter( MCT) to pump lactate( and pyruvate) out of the cell. Dr. Pete Pederson and Dr. Young Ko, researchers at Johns Hopkins, decided to exploit this, sending 3-bromopyruvate( 3-BrPa) into the cell via the MCT. 3-BrPa jams up the glycolysis gears and triggers apoptosis by squelching ATP production. It is effective in essentially all cancer types. The first patient to receive 3-BrPa was a nearly dead Dutch teenager with hepatocellular cancer residing in 95 percent of his liver. Eight months after( less than $ 100! worth of) 3-BrPa infusions, he became healthy enough to travel to the U. S. and speak at a conference. Sadly, he died of pneumonia after getting home to the Netherlands( he was radiographically cancer free when he died). Due to political, funding and patent issues, 3-BrPa is a bit stagnant in human research endeavors; but more molecular targets of these aberrant pathways are being investigated: SB-204990, 2-deoxy-D-glucose( 2DG), 3-BrOP, 5-thioglucose and dichloroacetic acid( DCA).
Dr. Pete Pederson stumbled upon another feature of many cancers: the most aggressive, glucose-fermenting, rapidly-growing bastards contain 50 percent less mitochondria. Oh, the fascinating
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