Differential roles of Trk and p75 neurotrophin receptors in tumorigenesis and chemoresistance ex vivo and in vivo.
The neurotrophin receptors TrkA (NGF receptor) and TrkC (NT-3 receptor) have been shown to be important in staging disease and predicting progression and drug response for various neoplasias such as neuroblastoma, medulloblastoma and prostate cancer. Less is known about the role of the p75 neurotrophin receptor in cancer, but it influences metastatic potential in glioblastoma. To determine the effect of each neurotrophin receptor or co-receptor expression in tumorigenesis, we examined PC12 pheochromocytomas. PC12 wild type (TrkA(+), p75(++)) were compared to three PC12-derived cell lines expressing varying levels of TrkA or TrkC and/or p75. Growth rates, tumorigenic potential ex vivo and in vivo, and chemotherapeutic drug response profiles differed depending on the neurotrophin receptor phenotype. The ability of neurotrophins to rescue cells from doxorubicin or cisplatin induced cell death also varied depending on phenotype. Thus, unique neurotrophin receptor tumor profiles may determine tumor aggressiveness and chemoresistance. This work may help to develop tailored therapies for specific tumor phenotypes by combining traditional chemotherapy with neurotrophin receptor modulators.
Bassili
Muriel
M
Lady Davis Research Institute, Jewish General Hospital, McGill University, 3755 Cote Ste-Catherine E-535, Montreal, QC, H3T 1E2, Canada.
Birman
Elena
E
Schor
Nina F
NF
Saragovi
H Uri
HU
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D016716:PC12 Cells; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000502:physiology*; D020917:Receptor, trkA / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D020800:Receptor, Nerve Growth Factor; D004317:Doxorubicin; D020917:Receptor, trkA; D002945:Cisplatin
Mol Pharmacol. 2002 Apr;61(4):710-9
11901208
Nat Neurosci. 2002 Nov;5(11):1131-6
12404007
Cancer Res. 2002 Nov 15;62(22):6462-6
12438236
Oncogene. 2009 May 14;28(19):2015-23
19363525
Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12867-71
7809137
J Invest Dermatol. 1994 Jul;103(1):13-8
8027574
J Biol Chem. 2005 Aug 12;280(32):29199-207
15961390
Oncogene. 2003 Aug 28;22(36):5677-85
12944916
Mol Cell Biol. 1990 Sep;10(9):5015-20
2167446
J Cutan Pathol. 2003 Jul;30(6):351-7
12834482
Oncol Rep. 2007 Sep;18(3):673-7
17671718
EMBO J. 1996 Jul 1;15(13):3332-7
8670834
PLoS Biol. 2007 Aug;5(8):e212
17696644
Science. 2002 May 31;296(5573):1648-9
12040181
J Neurosci. 1997 Aug 15;17(16):6031-7
9236214
Cancer Res. 2000 Nov 1;60(21):6045-51
11085526
In Vitro Cell Dev Biol. 1990 Jan;26(1):97-101
2307643
Pediatr Pathol Lab Med. 1997 Jan-Feb;17(1):1-25
9050057
J Neurooncol. 1999;45(1):27-36
10728907
Cell Mol Life Sci. 2004 Jan;61(1):35-48
14704852
BMC Neurosci. 2006 Jan 30;7:9
16445859
J Cell Biol. 1998 Dec 14;143(6):1691-703
9852160
Anticancer Drugs. 2006 Sep;17(8):929-41
16940803
EMBO J. 2009 Feb 4;28(3):261-73
19131967
Cancer Lett. 2001 Aug 28;169(2):107-14
11431098
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11133-7
7972023
N Engl J Med. 1993 Mar 25;328(12):847-54
8441429
Neurobiol Aging. 2007 Oct;28(10):1522-31
16887237
Clin Phys Physiol Meas. 1990;11 Suppl A:121-3
2286040
J Neurochem. 2007 Oct;103(1):259-75
17635673
J Biol Chem. 2000 Jan 7;275(1):565-70
10617652
Curr Opin Neurobiol. 2002 Jun;12(3):260-7
12049931
J Clin Oncol. 2000 Mar;18(5):1027-35
10694553
J Biol Chem. 2007 Jun 8;282(23):16754-63
17439940
J Biol Chem. 2001 Aug 17;276(33):31023-9
11425862
Int J Oncol. 2007 Jan;30(1):193-200
17143529