Migration deficit in monocyte-macrophages in human ovarian cancer.
OBJECTIVE
To examine the migration responses of monocyte/macrophages (MO/MA) expressing complementary receptors to chemokines produced in the tumor environment of epithelial ovarian cancer (EOC).


METHODS
We examined the expression of the chemokine receptors, CCR1, CCR5, and CXCR4, on EOC associated ascitic and blood MO/MA; their response to complementary chemokines in a MO/MA migration assay and the F-actin content in an actin polymerization assay. A validated cDNA microarray assay was then utilized to examine alterations in pathway genes that can be identified with cell migration.


RESULTS
Ascitic and EOC blood MO/MA express CCR1, CCR5 and CXCR4, but differently. Cell surface expression levels for CCR1 and CCR5 were higher in ascites than that of normal blood in contrast to CXCR4 levels in ascitic MO/MA which were lower. EOC associated ascitic or blood MO/MA failed to migrate in response to the CC ligand RANTES and to the CXCR4 reactive chemokine, SDF1 (CXCL12). Ascitic and most EOC blood MO/MA also behaved differently from normal blood MO in the polymerization/depolymerization assay. A cDNA gene analysis of purified ascitic MO/MA demonstrated that a number of genes involved with chemokine production, focal adhesion, actin cytoskeletal function and leukocyte transendothelial migration were down-regulated in the ascitic MO/MA when compared to normal blood MO. Moreover, PBMC cDNA from EOC patients' blood also showed gene profiles similar to that of ascitic MO/MA.


CONCLUSIONS
Defective migration and polymerization/depolymerization activity of MO/MA from EOC patients and a significant down-regulation of critical pathway genes suggest that other mechanisms might be involved in the accumulation of systemically derived MO at the tumor site of EOC patients.
Freedman
Ralph S
RS
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230, USA. rfreedma@mdanderson.org
Ma
Qing
Q
Wang
Ena
E
Gallardo
Stacie T
ST
Gordon
Ilyssa O
IO
Shin
Jeong Won
JW
Jin
Ping
P
Stroncek
David
D
Marincola
Francesco M
FM
D000199:Actins / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D054389:Receptors, CCR1 / Q000096:biosynthesis; D019713:Receptors, CCR5 / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000096:biosynthesis
D000199:Actins; C515300:CCR1 protein, human; C527276:CXCR4 protein, human; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019718:Receptors, CXCR4