Microenvironmental regulation of chemokine (C-X-C-motif) receptor 4 in ovarian carcinoma.
The majority of women diagnosed with epithelial ovarian carcinoma (EOC) succumb due to complications of metastatic disease, suggesting that antimetastatic therapies may improve patient survival. EOC metastasis involves intraperitoneal shedding of cells from the primary tumor, followed by adhesion and localized penetration of the submesothelial matrix to anchor metastatic implants. Accumulation of malignant ascites is also common. Thus, a unique microenvironmental niche is established, which includes malignant cells and a plethora of soluble factors secreted by-or in response to-tumor cells. As cells penetrating the submesothelial surface encounter an interstitial collagen-rich extracellular matrix, we have used three-dimensional type I collagen gels to model early events resulting from intraperitoneal anchoring. In this study, we show a novel pathway of CXCR4 upregulation through beta1 integrin - and NFkappaB-dependent signaling pathways in response to three-dimensional type I collagen. We also show the involvement of CXCR4-SDF1 axis in collagen invasion and proliferation, relevant to the metastatic EOC. Our data show that CXCR4 expression in human EOCs, as well as SDF1 presence in the ascites, is correlated with disease progression and metastasis. These data emphasize the importance of the CXCR4-SDF1 axis in EOC metastasis and suggest that this mechanism should be accounted for when targeting EOC metastasis.
Barbolina
Maria V
MV
Department of Biopharmaceutical Sciences, University of Illinois at Chicago, 833 South Wood Street, PHARM 355, Chicago, IL 60612, USA. mvb@uic.edu
Kim
Mijung
M
Liu
Yueying
Y
Shepard
Jaclyn
J
Belmadani
Abdelhak
A
Miller
Richard J
RJ
Shea
Lonnie D
LD
Stack
M Sharon
MS
D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12 / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D009924:Organ Culture Techniques; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D034741:RNA, Small Interfering / Q000502:physiology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019012:Integrin beta1; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D003094:Collagen
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