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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