PMID- 20080688
OWN - NLM
STAT- MEDLINE
DCOM- 20100312
LR  - 20220321
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 107
IP  - 4
DP  - 2010 Jan 26
TI  - Development of a mouse model for sporadic and metastatic colon tumors and its use 
      in assessing drug treatment.
PG  - 1565-70
LID - 10.1073/pnas.0908682107 [doi]
AB  - Most genetically engineered mouse (GEM) models for colon cancer are based on 
      tissuewide or germline gene modification, resulting in tumors predominantly of 
      the small intestine. Several of these models involve modification of the 
      adenomatous polyposis coli (Apc) gene and are excellent models for familial 
      cancer predisposition syndromes. We have developed a stochastic somatic mutation 
      model for sporadic colon cancer that presents with isolated primary tumors in the 
      distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen 
      in human colon cancer. Using this model, we have analyzed tumors that are either 
      solely mutant in the Apc gene or in combination with another colon 
      cancer-associated mutant gene, the Kras G12D allele. Because of the restricted 
      location in the distal colon, the natural history of the tumors can be analyzed 
      by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a 
      critical component of the complex signaling network in colon cancer, we used this 
      model to assess the efficacy of mTOR blockade through rapamycin treatment of mice 
      with established tumors. After treatment, Apc mutant tumors were more than 80% 
      smaller than control tumors. However, tumors that possessed both Apc and Kras 
      mutations did not respond to rapamycin treatment. These studies suggest that mTOR 
      inhibitors should be further explored as potential colorectal cancer therapies in 
      patients whose tumors do not have activating mutations in KRAS.
FAU - Hung, Kenneth E
AU  - Hung KE
AD  - Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111, USA. 
      khung@tuftsmedicalcenter.org
FAU - Maricevich, Marco A
AU  - Maricevich MA
FAU - Richard, Larissa Georgeon
AU  - Richard LG
FAU - Chen, Wei Y
AU  - Chen WY
FAU - Richardson, Michael P
AU  - Richardson MP
FAU - Kunin, Alexandra
AU  - Kunin A
FAU - Bronson, Roderick T
AU  - Bronson RT
FAU - Mahmood, Umar
AU  - Mahmood U
FAU - Kucherlapati, Raju
AU  - Kucherlapati R
LA  - eng
GR  - U01 CA084301/CA/NCI NIH HHS/United States
GR  - R01 EB001872/EB/NIBIB NIH HHS/United States
GR  - P50 CA127003/CA/NCI NIH HHS/United States
GR  - K08 DK078033/DK/NIDDK NIH HHS/United States
GR  - 5U01CA084301/CA/NCI NIH HHS/United States
GR  - 5P50CA127003/CA/NCI NIH HHS/United States
GR  - P30 DK043351/DK/NIDDK NIH HHS/United States
GR  - 5R01EB001872/EB/NIBIB NIH HHS/United States
GR  - 5K08DK078033/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100104
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (Hras protein, mouse)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/*therapeutic use
MH  - Colonic Neoplasms/*drug therapy/genetics/metabolism/*pathology
MH  - *Disease Models, Animal
MH  - Disease Progression
MH  - Genes, APC
MH  - Intracellular Signaling Peptides and Proteins/antagonists & inhibitors/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Mutation
MH  - Neoplasm Metastasis
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - Proto-Oncogene Proteins p21(ras)/genetics/metabolism
MH  - Signal Transduction
MH  - Sirolimus/*therapeutic use
MH  - TOR Serine-Threonine Kinases
PMC - PMC2824379
COIS- The authors declare no conflict of interest.
EDAT- 2010/01/19 06:00
MHDA- 2010/03/13 06:00
PMCR- 2010/01/04
CRDT- 2010/01/19 06:00
PHST- 2010/01/19 06:00 [entrez]
PHST- 2010/01/19 06:00 [pubmed]
PHST- 2010/03/13 06:00 [medline]
PHST- 2010/01/04 00:00 [pmc-release]
AID - 0908682107 [pii]
AID - 200908682 [pii]
AID - 10.1073/pnas.0908682107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1565-70. doi: 
      10.1073/pnas.0908682107. Epub 2010 Jan 4.