Signaling pathways in renal cell carcinoma.
Renal cell carcinoma (RCC), the most lethal type of genitourinary cancer, is generally resistant to chemotherapy and radiation therapy. Surgical excision of the tumor at a localized stage remains the mainstay for curative therapy. A number of drugs developed in recent years have shown limited to significant efficacy in treating RCC. These drugs act by blocking critical signaling pathways associated with RCC tumor growth and survival, and angiogenesis. Beyond well-validated signaling targets such as VHL, VEGFR and mTOR, additional pathways including HGF/c-MET and Wnt/β-catenin have emerged as important to RCC pathogenesis. Mutations in one or more components of these signaling networks may affect tumor response to therapy. This review summarizes the state of knowledge about signaling pathways in RCC and discusses the known genetic and epigenetic alterations that underlie dysregulation of these pathways.
Banumathy
Gowrishankar
G
Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
Cairns
Paul
P
D000970:Antineoplastic Agents / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D008954:Models, Biological; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology
D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor
Expert Rev Anticancer Ther. 2009 Jun;9(6):785-93
19496715
Cancer Res. 1995 Jan 15;55(2):224-7
7812948
Cancer Res. 2010 Feb 1;70(3):1053-62
20103629
Genes Chromosomes Cancer. 1999 Sep;26(1):20-8
10441001
Oncogene. 2005 Nov 14;24(50):7391-3
16288285
Clin Cancer Res. 2003 Jan;9(1):327-37
12538485
Nat Rev Cancer. 2005 Sep;5(9):699-712
16110318
Biochem Biophys Res Commun. 2005 Dec 9;338(1):627-38
16153592
Cell. 1998 Oct 2;95(1):29-39
9778245
Science. 1997 Oct 24;278(5338):687-9
9381178
Cancer Res. 2003 Dec 15;63(24):8695-9
14695183
Nat Rev Cancer. 2003 Oct;3(10):721-32
13130303
Cancer Metastasis Rev. 2007 Jun;26(2):225-39
17440684
J Natl Compr Canc Netw. 2009 Jun;7(6):659-65
19555587
Nat Genet. 1997 May;16(1):68-73
9140397
Proc Natl Acad Sci U S A. 1999 May 25;96(11):6199-204
10339565
Nat Rev Cancer. 2003 Jan;3(1):11-22
12509763
Mol Cell Biol. 2001 Feb;21(3):893-901
11154276
J Clin Oncol. 2009 May 1;27(13):2278-87
19332717
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14391-6
19706526
Cell. 2006 Nov 3;127(3):469-80
17081971
J Cell Mol Med. 2009 Sep;13(9B):3918-28
19228262
Eur Urol. 2009 Dec;56(6):959-71
19748725
Nat Rev Cancer. 2008 Aug;8(8):579-91
18596824
J Clin Oncol. 2010 Feb 20;28(6):1061-8
20100962
Nat Cell Biol. 2008 Oct;10(10):1208-16
18806787
Cell. 2006 Sep 8;126(5):955-68
16959574
Cancer Res. 2007 Apr 1;67(7):3171-6
17409424
Clin Cancer Res. 2009 Sep 15;15(18):5678-87
19755393
Nature. 2006 May 25;441(7092):424-30
16724053
N Engl J Med. 2005 Dec 8;353(23):2477-90
16339096
Cell. 1982 Nov;31(1):99-109
6297757
Nat Rev Urol. 2010 May;7(5):277-85
20448661
Future Oncol. 2009 Oct;5(8):1145-68
19852727
Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):3972-9
15217927
Pathol Int. 2000 Sep;50(9):725-30
11012986
Nat Rev Clin Oncol. 2009 Aug;6(8):478-87
19546865
Cancer Cell. 2008 Dec 9;14(6):435-46
19061835
Nat Cell Biol. 2003 Jan;5(1):7-8
12511881
Oncogene. 2005 Dec 8;24(55):8205-10
16116480
J Urol. 2004 Oct;172(4 Pt 1):1256-61
15371818
Clin Cancer Res. 2003 Oct 15;9(13):4641-52
14581333
Clin Cancer Res. 2009 Apr 1;15(7):2207-14
19318488
Oncogene. 1998 Jun 18;16(24):3215-8
9671402
Ann Clin Lab Sci. 2006 Summer;36(3):283-93
16951269
Biochem Pharmacol. 2002 Sep;64(5-6):993-8
12213597
Cancer Metastasis Rev. 2007 Dec;26(3-4):691-704
17768599
Nat Rev Mol Cell Biol. 2006 Feb;7(2):131-42
16493418
Mol Cancer. 2009 Jun 03;8:31
19493342
Genes Dev. 2004 Aug 15;18(16):1926-45
15314020
Nat Med. 2003 Apr;9(4):407-15
12652295
Science. 1998 Nov 13;282(5392):1318-21
9812896
J Cell Sci. 2007 Sep 15;120(Pt 18):3163-72
17878233
Science. 2009 May 22;324(5930):1029-33
19460998
Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14531-6
16983094
J Pathol. 2008 Dec;216(4):418-27
18925646
Ann Oncol. 2005 Jun;16(6):928-33
15851405
Oncogene. 1998 Aug 13;17(6):733-9
9715275
Oncogene. 2001 Sep 20;20(42):5972-81
11593404
EMBO Rep. 2008 Jun;9(6):582-9
18483486
Genes Dev. 2008 Apr 1;22(7):894-907
18381893
Annu Rev Med. 2003;54:217-33
12525673
Cancer Res. 2002 Apr 1;62(7):2064-71
11929826
Nat Genet. 2007 Mar;39(3):347-51
17293865
Urology. 2010 Apr;75(4):835-41
20035975
Clin Transl Oncol. 2008 Nov;10(11):697-712
19015066
Clin Cancer Res. 2008 Oct 1;14(19):5941-6
18829470
J Biol Chem. 2009 Nov 13;284(46):32066-74
19762474
Clin Cancer Res. 2006 Jan 15;12(2):383-91
16428476
Clin Cancer Res. 2010 Mar 1;16(5):1368-72
20179227
Oncol Rep. 2008 Nov;20(5):1257-63
18949430
J Clin Oncol. 2004 Feb 1;22(3):454-63
14752067
BJU Int. 2009 Dec;104(11):1585-9
20053190
Cancer Res. 2002 Aug 15;62(16):4554-7
12183404
Nat Cell Biol. 2008 May;10(5):593-601
18376396
Mol Cell. 2009 Sep 24;35(6):856-67
19782034
Cancer Res. 2006 Jun 1;66(11):5549-54
16740688
N Engl J Med. 2007 May 31;356(22):2271-81
17538086
Nat Rev Cancer. 2004 May;4(5):381-93
15122209
Br J Cancer. 2007 Jan 29;96(2):336-40
17133269
Trends Biochem Sci. 2009 Mar;34(3):101-4
19217300
Lab Invest. 2008 Sep;88(9):962-72
18626467
Kidney Int. 1999 Oct;56(4):1603-4
10610416
J Biol Chem. 2005 Feb 4;280(5):3938-45
15550389
Nat Rev Drug Discov. 2006 Dec;5(12):997-1014
17139285
Cold Spring Harb Symp Quant Biol. 2005;70:159-66
16869749
Int J Biochem Cell Biol. 2009 Apr;41(4):753-6
18950731
Nat Cell Biol. 2008 Mar;10(3):295-305
18297062
Oncogene. 1999 Apr 8;18(14):2343-50
10327054
Oncogene. 2010 Feb 4;29(5):625-34
19946328
Oncogene. 2009 Jan 15;28(2):297-305
18931698
Cancer Res. 2009 Jun 1;69(11):4674-81
19470766
Cancer Res. 1996 Apr 15;56(8):1892-5
8620510
Eur Urol. 2010 Jul;58(1):75-83
20359812
Nature. 2010 Jan 21;463(7279):360-3
20054297
Nat Rev Cancer. 2002 Sep;2(9):673-82
12209156
Cancer Res. 2009 Nov 15;69(22):8603-10
19887605
Cell. 2006 Feb 10;124(3):471-84
16469695
J Clin Oncol. 2006 Jan 1;24(1):25-35
16314617
Genes Dev. 1998 Nov 15;12(22):3499-511
9832503
Clin Cancer Res. 2007 Jun 1;13(11):3109-14
17545512
Cancer. 2009 Oct 1;115(19):4488-503
19562778
Nat Rev Clin Oncol. 2009 Oct;6(10):587-95
19787002