Jesus  Maldonado  
  B.S.  Biochemistry/Biomedical  Engineering  
    The  University  of  Texas  at  Austin  

How  Cancer  Works  

Introduction  
  Cancer  is  a  prevalent  disease  that  kills  1%  of  the  US  population  every  year.  
Despite  existing  throughout  human  history,  only  recently  have  the  molecular  
characteristics  of  cancer  come  to  light.    This  article  describes  the  set  of  10  
characteristics:  eight  hallmarks  and  two  enabling  characteristics  that,  together,  can  
lead  to  the  deadly  disease  state  known  as  cancer.  

How  Cancer  Starts:  Genome  Instability  and  Mutations  

  The  first  and  most  important  characteristic  of  cancer  that  all  cells  must  
accumulate  is  the  ability  to  acquire  genetic  mutations.  Cancer  cells,  in  order  to  
acquire  all  characteristics  they  show,  require  mutations  in  their  genome,  which  
means  mutations,  deletions,  or  insertions  into  the  genetic  code  that  null  otherwise  
normal  genes.  Certain  proteins,  such  as  p53,  act  against  these  mutations:  by  
ensuring  that  certain  cells  die  if  they  acquire  too  many  mutations.  Cancer  cells  can  
acquire  mutations  in  this  gene,  and  other  guardians  of  the  genome,  which  would  
destroy  the  cell’s  capability  to  protect  itself  against  mutations.  Because  this  
characteristic  of  cancer  cells  can  lead  to  others,  and  is  the  basis  of  cancer,  genome  
instability  and  mutations.    

An  Enabling  Characteristic:  Inflammation    

  Cancer  cells  may  require  increased  amounts  of  nutrients  to  grow,  as  they  
supersede  the  barriers  of  normal  tissue  growth.  They  amass  different  amounts  of  
cells,  both  normal  and  cancerous,  to  carry  out  all  the  normal  processes  that  an  organ  
normally  does.  Inflammation  normally  occurs  around  cancerous  cells  to  provide  
biological  molecules  that  help  the  cancer  cell  in  some  way:  growth  factors  that  direct  
the  cell  to  grow  in  size,  angiogenesis  factors  which  recruit  blood  vessels,  and  
apoptosis  evasion  proteins,  which  circumvent  the  normal  process  of  cell  death.  With  
inflammation,  cancerous  cells  can  become  tumors:  a  collection  of  normal  and  
cancerous  cells  that  displays  increased  size  and  number  not  normally  present  in  
normal  cell  tissue.  
 
 
 

 
 
     Jesus  Maldonado  
  B.S.  Biochemistry/Biomedical  Engineering  
    The  University  of  Texas  at  Austin  
 
List  of  Hallmarks:  
  The  following  figure  serves  as  the  basis  for  the  discussion  below  about  the  
mechanisms  that  cancer  undergoes.    

 
A  cancer  cell  may  at  any  point  acquire  one  of  the  following  hallmarks  of  cancer,  even  
without  an  enabling  characteristic  (as  shown  above).  The  point  at  which  cancerous  
cells  acquire  these  capabilities  is  not  dependent  on  any  other  point:  they  can  acquire  
these  capabilities,  either  multiple  ones  or  all,  and  cancer  can  result  as  a  result  of  
these  mutations.    
1. Deregulation  of  Cellular  Metabolism  
a. Cancer  cells  show  an  increased  usage  of  an  inefficient  energy-­‐
harvesting  process:  the  conversion  of  glucose,  one  of  the  basic  sugars,  
to  pyruvate,    a  compound  used  to  yield  high  amounts  of  energy  in  a  
process  called  chemiosmotic  phosphorylation.  Normally,  the  
conversion  of  glucose  to  pyruvate  is  just  a  first  step  in  the  process  of  
energy  harvesting  in  a  cell.  In  order  to  supply  the  increased  energetic  
demands  of  the  cell,  cancer  cells  increase  the  amount  of  glucose  
     Jesus  Maldonado  
  B.S.  Biochemistry/Biomedical  Engineering  
    The  University  of  Texas  at  Austin  
transported  inside  by  increasing  the  synthesis  of  glucose  transporters.  
Despite  the  low  energy  efficiency,  scientists  hypothesize  that  the  
increase  in  glucose  metabolism  occurs  because  the  process  yields  
several  intermediates.  These  go-­‐betweens  are  important  building  
blocks  for  other  compounds  necessary  for  the  cancerous  cell,  amino  
acids.    
2. Invasion  and  Metastasis  
a. Tumor  cells  can  acquire  the  ability  to  invade  other  nearby  tissues  and  
even  other  parts  of  the  body  through  the  lymphatic  and  circulatory  
system.  Invasive  cancer  cells  lose  the  proteins  that  anchor  them  to  
other  cells,  such  as  E-­‐cadherin,  enabling  the  movement  of  cancer  cells  
to  other  parts  of  the  body.  The  body  has  natural  defenses  against  the  
spread  of  cancers  to  other  tissues  (metastasis)  but  in  metastatic  
cancer,  these  mechanisms  are  weakened.  Once  a  cancer  cell  has  
invaded  another  tissue,  by  genomic  instability  and  mutation,  it  can  
activate  the  adhesion  molecules  necessary  to  anchor  itself  in  its  new  
environment.  
3. Resistance  of  Apoptosis    
a. Our  own  cells  die  in  a  process  called  apoptosis.  The  body  naturally  
orders  cells  to  commit  suicide  in  order  to  preserve  the  integrity  of  the  
body:  cells  with  high  concentrations  of  toxic  material,  excessive  
amounts  of  mutations,  or  inefficient  cells  are  killed  off  by  our  own  
cells.  Cancer  cells  must  evade  this  portion  of  the  normal  cell  cycle.    
They  do  so  by  destroying  the  proteins  that  enable  the  process,  or  
creating  more  inhibitors  (such  as  Bcl-­‐2)  of  the  process.  Or,  they  may  
altogether  destroy  sensors  that  allow  for  the  detection  of  abnormal  
activity  in  the  cell.  
4. Sustain  Proliferative  Signaling  
a. Cancer  cells  undergo  constant  cell  division,    increasing  the  total  
number  of  cells.  Arguably  this  may  be  the  most  fundamental  
characteristic  of  all  cancer  cells  (this  is  why  it’s  in  every  scenario  in  
the  diagram  above!)  In  order  to  do  this,  cancer  cells  can  lay  down  
proteins  that  signal  other  cells  to  supply  growth  signals  or  activate  
growth  signals  themselves,  without  the  presence  of  a  stimulus  to  elicit  
the  response.  Defective  cells  can  permanently  link  certain  receptors  
that  would  normally  only  occur  because  of  an  external  signals,  
ensuring  that  cancer  cells  undergo  constant  cell  division.  
5. Enabling  Replicative  Immortality  
a. Cells  are  only  allowed  to  proliferate  a  certain  amount  of  times,  termed  
the  Hayflick  limit  of  the  cell.  The  Hayflick  limit  is  determined  by  the  
shortening  of  sequences  at  the  end  of  chromosomes  called  telomeres.  
Each  time  a  cell  divides,  these  ends  are  shortened  by  a  certain  
amount.  Once  there  is  no  telomere  left,  the  cell  enters  into  crisis,  the  
sudden  death  of  a  cell.  An  enzyme,  telomerase,  extends  these  
     Jesus  Maldonado  
  B.S.  Biochemistry/Biomedical  Engineering  
    The  University  of  Texas  at  Austin  
telomeres,  and  the  majority  of  cancers  must  express  this  enzyme  in  
order  to  continuously  replicate.  
6. Sustained  Angiogenesis  
a. Tumors  need  vast  amounts  of  nutrients  in  order  to  sustain  their  
proliferative  state.  Increased  blood  vessel  growth  must  occur  in  order  
to  supply  these  nutrients.  Cancer  cells  increase  the  concentration  of    
the  factors  that  determine  angiogenesis  (such  as  VEGF)  and  decrease  
inhibitors  of  the  process.  Without  either  of  these  processes,  a  tumor  
cannot  grow  beyond  a  certain  natural  limit  that  would  allow  it  to  
invade  nearby  tissue.  Because  of  the  unchecked  expression  of  these  
proteins,  tumors  show  strange  blood  vessel  growth  marked  by  
contortions  and  irregularities  in  the  blood  vessels.  
7. Evasion  of  Growth  Suppressors  
a. Cells  contain  two  main  proteins  that  restrain  unrestricted  growth:  
p53  and  Rb.  The  loss  of  either  of  these  proteins  does  not  mark  the  
onset  of  cancer  usually.  Mice  studies  have  shown  that  a  loss  in  either  
protein  predisposes  mice  to  cancer  later  in  life;  but  a  loss  in  both  of  
these  proteins,  a  characteristic  of  tumors,  will  result  in  the  formation  
of  a  cancerous  cell,  that  can  acquire  the  other  characteristics  of  
cancer.  
8. Avoiding  Immune  Destruction  
a. Cancer  cells  must  evade  the  immune  system  if  they  are  to  proliferate  
to  another  portion  of  the  body.  They  do  so  by  two  main  mechanisms:  
destruction  of  the  cells  that  would  destroy  them,  by  secreting  
immunosuppressive  proteins  such  as  TGF-­‐β,  or  by  recruiting  
immunosuppressive  cells,  like  regulatory  T  cells.  
These  eight  hallmarks  and  two  enabling  characteristics  enumerate  the  various  
aspects  of  cancer.  As  can  be  seen,  the  pathways  are  all  interconnected;  hallmarks  
require  other  characteristics  to  be  fully  functional,  or  may  only  be  cancerous  when  
combined  with  other  aspects.  For  the  same  kind  of  cancer,  different  factors  could  
lead  to  the  same  disease  state  in  different  patients.  With  a  thorough  understanding  
of  each  person’s  biochemistry  and  these  ten  characteristics,  a  specific  program  
could  be  made  to  combat  cancer.  
 

Reference:  
Hanahan,  D.  and  Weinberg,  R.A.  Hallmarks  of  Cancer:  The  Next  Generation.  Cell,  
144(5),  646-­‐674,  2011.