Coordinated expression of integrin subunits, matrix metalloproteinases (MMP), angiogenic genes and Ets transcription factors in advanced-stage ovarian carcinoma: a possible activation pathway?
The events that mediate tumor progression in ovarian carcinoma are poorly understood to date. This review summarizes our results studying metastasis-associated molecules in advanced-stage ovarian carcinomas, details the co-expression of mRNA of these genes, and discusses their prognostic role. Fifty-five primary and metastatic FIGO stage III-IV ovarian carcinomas were analyzed for the expression of alpha v and beta1 integrin subunits, the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP, the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), PEA3 and Ets-1 using mRNA in situ hybridization. Tumor and adjacent stromal cell expression was scored. The association between integrin subunit expression and the expression of MMP, TIMP-2, angiogenic genes, PEA3 and Ets-1 was statistically analyzed. Alpha v integrin subunit mRNA expression in carcinoma cells showed significant association with that of MMP-2 and IL-8 in this cellular compartment, while the presence of beta1 integrin subunit mRNA showed similar association with that of PEA3, Ets-1, IL-8, bFGF and MMP-2. Expression of beta1 integrin subunit mRNA in stromal cells was associated with that of TIMP-2 and Ets-1 in this compartment. In addition, significant intercellular associations were found between alpha v integrin subunit mRNA expression in carcinoma cells and stromal cell expression of Ets-1, as well as between stromal cell expression of alpha v integrin subunit and labeling for IL-8 in carcinoma cells. The presence of beta1 integrin subunit mRNA in carcinoma cells showed a significant association with that of Ets-1, IL-8 and bFGF in stromal cells, while the presence of beta1 integrin subunit mRNA in stromal cells was associated with tumor PEA3 mRNA expression. To the best of our knowledge, this is the first evidence for coordinated autocrine and paracrine expression of members of these four families of metastasis-associated genes in human cancer. The results of this analysis support experimental data regarding cross-talk between carcinoma cells and peritumoral fibroblasts. They also suggest the existence of a putative activation sequence of metastatic genes, involving the beta1 (and possibly alpha v) integrin subunits, IL-8, PEA3, Ets-1 and MMP in ovarian carcinoma.
Davidson
Ben
B
Department of Pathology, The Norwegian Radium Hospital, Montebello N-0310 Oslo, affiliated with the University of Oslo, Norway. bend@ulrik.uio.no
Goldberg
Iris
I
Gotlieb
Walter H
WH
Kopolovic
Juri
J
Risberg
Bjørn
B
Ben-Baruch
Gilad
G
Reich
Reuven
R
D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042501:Angiogenic Proteins / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000473:pathology; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D016023:Integrins / Q000235:genetics* / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D042501:Angiogenic Proteins; D014408:Biomarkers, Tumor; C494041:ETS1 protein, human; D016023:Integrins; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D014157:Transcription Factors; D008666:Metalloendopeptidases