Research IndicatorsGraph generated 25 June 2015 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: CCR1 (cancer-related)
To understand colon cancer metastasis, we earlier analyzed a mouse model that developed liver metastasis of cancer cells disseminated from the spleen. We suggested that CCR1(+) bone marrow (BM)-derived cells are recruited to the microenvironment of disseminated colon cancer cells, and produce metalloproteinases MMP9 and MMP2, helping metastatic colonization. In the present study, we have examined these myeloid cells expressing CCR1 and/or MMPs in detail. To this end, we have established bacterial artificial chromosome (BAC)-based transgenic mouse lines in which membrane-targeted Venus fluorescent protein (mVenus) was expressed under the control of Ccr1 gene promoter. Then, myeloid cells obtained from the BM and liver metastatic foci were analyzed by the combination of flow cytometry and cytology/immunohistochemistry, in situ RNA hybridization, or quantitative RT-PCR. We have found four distinct types of myeloid cells recruited to the metastatic foci; neutrophils, eosinophils, monocytes and fibrocytes. These cell types exhibited distinct expression patterns for CCR1, MMP2 and MMP9. Namely, neutrophils found in the early phase of cancer cell dissemination expressed CCR1 exclusively and MMP9 preferentially, whereas fibrocytes accumulated in later phase expressed MMP2 exclusively. Either genetic inactivation of Ccr1 or antibody-mediated neutrophil depletion reduced subsequent recruitment of fibrocytes. The recruitment of CCR1(+) neutrophils in early phase of colon cancer dissemination appears to cause that of fibrocytes in late phase. These results implicate the key role of CCR1 in colon cancer metastasis in this mouse model, and explain why both MMP9 and MMP2 are essential as genetically demonstrated previously. The results also suggest relevant mechanisms in humans.
The adoptive transfer of T cells is a promising approach to treat cancers. Primary human T cells can be modified using viral and non-viral vectors to promote the specific targeting of cancer cells via the introduction of exogenous T-cell receptors (TCRs) or chimeric antigen receptors (CARs). This gene transfer displays the potential to increase the specificity and potency of the anticancer response while decreasing the systemic adverse effects that arise from conventional treatments that target both cancerous and healthy cells. This review highlights the generation of clinical-grade T cells expressing CARs for immunotherapy, the use of these cells to target B-cell malignancies and, particularly, the first clinical trials deploying the Sleeping Beauty gene transfer system, which engineers T cells to target CD19+ leukemia and non-Hodgkin's lymphoma.
In the initiation process of chronic myeloid leukemia (CML), a small number of transformed leukemia-initiating cells (LICs) coexist with a large number of normal hematopoietic cells, gradually increasing thereafter and eventually predominating in the hematopoietic space. However, the interaction between LICs and normal hematopoietic cells at the early phase has not been clearly delineated because of the lack of a suitable experimental model. In this study, we succeeded in causing a marked leukocytosis resembling CML from restricted foci of LICs in the normal hematopoietic system by direct transplantation of BCR-ABL gene-transduced LICs into the bone marrow (BM) cavity of nonirradiated mice. Herein, we observed that BCR-ABL(+)lineage(-)c-kit(-) immature leukemia cells produced high levels of an inflammatory chemokine, MIP-1α/CCL3, which promoted the development of CML. Conversely, ablation of the CCL3 gene in LICs dramatically inhibited the development of CML and concomitantly reduced recurrence after the cessation of a short-term tyrosine kinase inhibitor treatment. Finally, normal hematopoietic stem/progenitor cells can directly impede the maintenance of LICs in BM in the absence of CCL3 signal.
Itatani Y, Kawada K, Fujishita T, et al.Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis.
Gastroenterology. 2013; 145(5):1064-1075.e11 [PubMed
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BACKGROUND & AIMS: Loss of the tumor suppressor SMAD4 correlates with progression of colorectal cancer (CRC). In mice, colon tumors that express CCL9 recruit CCR1(+) myeloid cells, which facilitate tumor invasion and metastasis by secreting matrix metalloproteinase 9.
METHODS: We used human CRC cell lines to investigate the ability of SMAD4 to regulate expression of CCL15, a human ortholog of mouse CCL9. We used immunohistochemistry to compare levels of CCL15 and other proteins in 141 samples of human liver metastases.
RESULTS: In human CRC cell lines, knockdown of SMAD4 increased CCL15 expression, and overexpression of SMAD4 decreased it. SMAD4 bound directly to the promoter region of the CCL15 gene to negatively regulate its expression; transforming growth factor-β increased binding of SMAD4 to the CCL15 promoter and transcriptional repression. In livers of nude mice, SMAD4-deficient human CRC cells up-regulated CCL15 to recruit CCR1(+) cells and promote metastasis. In human tumor samples, there was a strong inverse correlation between levels of CCL15 and SMAD4; metastases that expressed CCL15 contained 3-fold more CCR1(+) cells than those without CCL15. Patients with CCL15-expressing metastases had significantly shorter times of disease-free survival than those with CCL15-negative metastases. CCR1(+) cells in the metastases expressed the myeloid cell markers CD11b and myeloperoxidase, and also matrix metalloproteinase 9.
CONCLUSIONS: In human CRC cells, loss of SMAD4 leads to up-regulation of CCL15 expression. Human liver metastases that express CCL15 contain higher numbers CCR1(+) cells; patients with these metastases have shorter times of disease-free survival. Reagents designed to block CCL15 recruitment of CCR1(+) cells could prevent metastasis of CRC to liver.
Chen Q, Zheng T, Lan Q, et al.Single-nucleotide polymorphisms in genes encoding for CC chemokines were not associated with the risk of non-Hodgkin lymphoma.
Cancer Epidemiol Biomarkers Prev. 2013; 22(7):1332-5 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Chemokines play a pivotal role in immune regulation and response, and previous studies suggest an association between immune deficiency and non-Hodgkin lymphoma (NHL).
METHODS: We evaluated the association between NHL and polymorphisms in 18 genes (CCL1, CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL18, CCL20, CCL24, CCL26, CCR1, CCR3, CCR4, CCR6, CCR7, CCR8, and CCR9) encoding for the CC chemokines using data from a population-based case-control study of NHL conducted in Connecticut women.
RESULTS: CCR8 was associated with diffuse large B-cell lymphoma (DLBCL; P = 0.012), and CCL13 was associated with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL; P = 0.003) at gene level. After adjustment for multiple comparisons, none of the genes or single-nucleotide polymorphisms (SNP) were associated with risk of overall NHL or NHL subtypes.
CONCLUSIONS: Our results suggest that the genes encoding for CC chemokines are not significantly associated with the risk of NHL, and further studies are needed to verify these findings.
IMPACT: Our data indicate that CC chemokine genes were not associated with NHL risk.
The molecular mechanism underlying tumor-induced epileptogenesis is poorly understood. Alterations in the peritumoral microenvironment are believed to play a significant role in inducing epileptogenesis. We hypothesize that the change of gene expression in brain peritumoral tissues may contribute to the increased neuronal excitability and epileptogenesis. To identify the genes possibly involved in tumor-induced epilepsy, a genome-wide gene expression profiling was conducted using Affymetrix HG U133 plus 2.0 arrays and RNAs derived from formalin-fixed paraffin embedded (FFPE) peritumoral cortex tissue slides from 5-seizure vs. 5-non-seizure low grade brain tumor patients. We identified many differentially expressed genes (DEGs). Seven dysregulated genes (i.e., C1QB, CALCRL, CCR1, KAL1, SLC1A2, SSTR1 and TYRO3) were validated by qRT-PCR, which showed a high concordance. Principal Component Analysis (PCA) showed that epilepsy subjects were clustered together tightly (except one sample) and were clearly separated from the non-epilepsy subjects. Molecular functional categorization showed that significant portions of the DEGs functioned as receptor activity, molecular binding including enzyme binding and transcription factor binding. Pathway analysis showed these DEGs were mainly enriched in focal adhesion, ECM-receptor interaction, and cell adhesion molecules pathways. In conclusion, our study showed that dysregulation of gene expression in the peritumoral tissues may be one of the major mechanisms of brain tumor induced-epilepsy. However, due to the small sample size of the present study, further validation study is needed. A deeper characterization on the dysregulated genes involved in brain tumor-induced epilepsy may shed some light on the management of epilepsy due to brain tumors.
Du L, Xu WT, Fan QM, et al.Tumorigenesis and spontaneous metastasis by luciferase-labeled human xenograft osteosarcoma cells in nude mice.
Chin Med J (Engl). 2012; 125(22):4022-30 [PubMed
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BACKGROUND: Osteosarcoma (OS) is the most common primary malignant tumor of bone. Mouse models of human OS can invariably provide greater insight into the complex mechanisms that underlie the development and pathogenesis of this aggressive tumor. Bioluminescence technology favored tracing cancer cells in vivo. In this study, an OS model was described and evaluated using human OS cell line, Saos2, labeled with luciferase (Saos2-luc).
METHODS: Saos2 cells were infected by lentivirus loading a firefly luciferase gene. Luciferase expression of Saos2-luc cells was characterized both in vitro and in vivo. Specific biologic and oncologic features of Saos2-luc cells were analyzed. The OS was established as orthotopic xenografts in nude mice. Both orthotopic tumors and spontaneous lung metastasis were analyzed.
RESULTS: Tumorigenesis and spontaneous lung metastasis in nude mice could be monitored in vivo through in vivo imaging system. The enhancement in proliferation, migration and invasion abilities and the attenuation in adhesion ability were observed in Saos2-luc cells compared with Saos2 cells. Furthermore, there were the up-regulation of Osteocalcin, CCR10, CXCR1 and ID1 and the down-regulation of ALP, collagen I, CCR1, CCR3, CXCR3, NID and N-cadherin in Saos2-luc cells compare to Saos2 cells. The rate of spontaneous lung metastasis in Saos2-luc cells was higher than that in Saos2 cells, although without significant difference.
CONCLUSIONS: Lentivirus transfection may cause alteration of gene expression profiles and further biological functions. This model can be used in the elucidation of molecular mechanisms of tumorigenesis and the screening of new therapeutic agents.
Long H, Xie R, Xiang T, et al.Autocrine CCL5 signaling promotes invasion and migration of CD133+ ovarian cancer stem-like cells via NF-κB-mediated MMP-9 upregulation.
Stem Cells. 2012; 30(10):2309-19 [PubMed
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The concept of cancer stem cells (CSCs) proposes that solely CSCs are capable of generating tumor metastases. However, how CSCs maintain their invasion and migration abilities, the most important properties of metastatic cells, still remains elusive. Here we used CD133 to mark a specific population from human ovarian cancer cell line and ovarian cancer tissue and determined its hyperactivity in migration and invasion. Therefore, we labeled this population as cancer stem-like cells (CSLCs). In comparison to CD133- non-CSLCs, chemokine CCL5 and its receptors, CCR1, CCR3, and CCR5, were consistently upregulated in CSLCs, and most importantly, blocking of CCL5, CCR1, or CCR3 effectively inhibits the invasive capacity of CSLCs. Mechanistically, we identified that this enhanced invasiveness is mediated through nuclear factor κB (NF-κB) activation and the consequently elevated MMP9 secretion. Our results suggested that the autocrine activation of CCR1 and CCR3 by CCL5 represents one of major mechanisms underlying the metastatic property of ovarian CSLCs.
Cho YB, Lee WY, Choi SJ, et al.CC chemokine ligand 7 expression in liver metastasis of colorectal cancer.
Oncol Rep. 2012; 28(2):689-94 [PubMed
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The main cause of death for colorectal cancer (CRC) patients is the development of metastatic lesions at sites distant from the primary tumor. Therefore, it is important to find biomarkers that are related to the metastasis and to study the possible mechanisms. Recent data have shown that soluble attractant molecules called chemokines support the metastasis of certain cancers to certain organs. To identify molecular regulators that are differentially expressed in liver metastasis of CRC, PCR array analysis was performed and CC chemokine ligand 7 (CCL7) showed remarkable overexpression in liver metastatic tumor tissues. To validate the results of the PCR array, 30 patients with primary CRC and liver metastases were selected. Immunohistochemistry and real-time PCR analysis showed that CCL7 was expressed in normal colonic epithelium and the expression was higher in liver metastases compared to primary CRC (p<0.001). Real-time PCR showed that the expression of CCR1, CCR2 and CCR3 was also higher in liver metastases compared to primary CRC (p=0.001, p=0.033 and p<0.001, respectively). In conclusion, correlation of CCL7 overexpression and its receptor expression with colon cancer liver metastasis suggests that CCL7 as a novel target in liver metastasis of CRC may be of potential clinical value for the prevention of hepatic recurrences.
Pham K, Luo D, Liu C, Harrison JKCCL5, CCR1 and CCR5 in murine glioblastoma: immune cell infiltration and survival rates are not dependent on individual expression of either CCR1 or CCR5.
J Neuroimmunol. 2012; 246(1-2):10-7 [PubMed
] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is the most malignant brain tumor. Microglia/macrophages are found within human GBM where they likely promote tumor progression. We report that CCL5, CCR1, and CCR5 are expressed in glioblastoma. Individual deletion of CCR1 or CCR5 had little to no effect on survival of tumor bearing mice, or numbers of glioblastoma-infiltrated microglia/macrophages or lymphocytes. CCL5 promoted in vitro migration of wild type, CCR1- or CCR5-deficient microglia/macrophages that was blocked by the dual CCR1/CCR5 antagonist, Met-CCL5. These data suggest that CCL5 functions within the glioblastoma microenvironment through CCR1 and CCR5 in a redundant manner.
BACKGROUND: XMRV is a gammaretrovirus first identified in prostate tissues of Prostate Cancer (PC) patients and later in the blood cells of patients with Chronic Fatigue Syndrome (CFS). Although XMRV is thought to use XPR1 for cell entry, it infects A549 cells that do not express XPR1, suggesting usage of other receptors or co-receptors.
METHODS: To study the usage of different receptors and co- receptors that could play a role in XMRV infection of lymphoid cells and GHOST (GFP- Human osteosarcoma) cells expressing CD4 along with different chemokine receptors including CCR1, CCR2, etc., were infected with XMRV. Culture supernatants and cells were tested for XMRV replication using real time quantitative PCR.
RESULTS: Infection and replication of XMRV was seen in a variety of GHOST cells, LNCaP, DU145, A549 and Caski cell lines. The levels of XMRV replication varied in different cell lines showing differential replication in different cell lines. However, replication in A549 which lacks XPR1 expression was relatively higher than DU145 but lower than, LNCaP. XMRV replication varied in GHOST cell lines expressing CD4 and each of the co- receptors CCR1-CCR8 and bob. There was significant replication of XMRV in CCR3 and Bonzo although it is much lower when compared to DU145, A549 and LNCaP.
CONCLUSION: XMRV replication was observed in GHOST cells that express CD4 and each of the chemokine receptors ranging from CCR1- CCR8 and BOB suggesting that infectivity in hematopoietic cells could be mediated by use of these receptors.
Upregulation of cytokines and chemokines is a frequent finding in multiple myeloma (MM). CCL3 (also known as MIP-1α) is a pro-inflammatory chemokine, levels of which in the MM microenvironment correlate with osteolytic lesions and tumor burden. CCL3 and its receptors, CCR1 and CCR5, contribute to the development of bone disease in MM by supporting tumor growth and regulating osteoclast (OC) differentiation. In this study, we identify inhibition of osteoblast (OB) function as an additional pathogenic mechanism in CCL3-induced bone disease. MM-derived and exogenous CCL3 represses mineralization and osteocalcin production by primary human bone marrow stromal cells and HS27A cells. Our results suggest that CCL3 effects on OBs are mediated by ERK activation and subsequent downregulation of the osteogenic transcription factor osterix. CCR1 inhibition reduced ERK phosphorylation and restored both osterix and osteocalcin expression in the presence of CCL3. Finally, treating SCID-hu mice with a small molecule CCR1 inhibitor suggests an upregulation of osteocalcin expression along with OC downregulation. Our results show that CCL3, in addition to its known catabolic activity, reduces bone formation by inhibiting OB function, and therefore contributes to OB/OC uncoupling in MM.
The purpose of this work was to analyze chemokine and chemokine receptor expression in untreated and in irradiated squamous cell carcinoma of the head and neck (SCCHN) tumor cell lines, aiming at the establishment of assays to test for the relevance of chemokine and chemokine receptor expression in the response of SCCHN to radiotherapy and radiochemotherapy. Five low passage and 10 established SCCHN lines, as well as two normal cell lines, were irradiated at 2 Gy or sham-irradiated, and harvested between 1 and 48 h after treatment. For chemokines with CC and CXC structural motifs and their receptors, transcript levels of target and reference genes were quantified relatively by real-time PCR. In addition, CXCL1 and CXCL12 protein expression was analyzed by ELISA. A substantial variation in chemokine and chemokine receptor expression between SCCHN was detected. Practically, all cell lines expressed CCL5 and CCL20, while CCL2 was expressed in normal cells and in some of the tumor cell lines. CXCL1, CXCL2, CXCL3, CXCL10, and CXCL11 were expressed in the vast majority of the cell lines, while the expression of CXCL9 and CXCL12 was restricted to fibroblasts and few tumor cell lines. None of the analyzed cell lines expressed the chemokines CCL3, CCL4, or CCL19. Of the receptors, transcript expression of CCR1, CCR2, CCR3, CCR5, CCR7, CCXR2, and CCXR3 was not detected, and CCR6, CXCR1, and CXCR4 expression was restricted to few tumor cells. Radiation caused up- and down-regulation with respect to chemokine expressions, while for chemokine receptor expressions down-regulations were prevailing. CXCL1 and CXCL12 protein expression corresponded well with the mRNA expression. We conclude that the substantial variation in chemokine and chemokine receptor expression between SCCHN offer opportunities for the establishment of assays to test for the relevance of chemokine and chemokine receptor expression in the response of SCCHN to radiotherapy and radiochemotherapy.
Kitamura T, Fujishita T, Loetscher P, et al.Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model.
Proc Natl Acad Sci U S A. 2010; 107(29):13063-8 [PubMed
] Free Access to Full Article Related Publications
Recent reports have suggested critical roles of myeloid cells in tumor invasion and metastasis, although these findings have not led to therapeutics. Using a mouse model for liver dissemination, we show that mouse and human colon cancer cells secrete CC-chemokine ligands CCL9 and CCL15, respectively, and recruit CD34(+) Gr-1(-) immature myeloid cells (iMCs). They express CCL9/15 receptor CCR1 and produce matrix metalloproteinases MMP2 and MMP9. Lack of the Ccr1, Mmp2, or Mmp9 gene in the host dramatically suppresses outgrowths of disseminated tumors in the liver. Importantly, CCR1 antagonist BL5923 blocks the iMC accumulation and metastatic colonization and significantly prolongs the survival of tumor-bearing mice. These results suggest that CCR1 antagonists can provide antimetastatic therapies for patients with disseminated colon cancer in the liver.
Yang D, Tong L, Wang D, et al.Roles of CC chemokine receptors (CCRs) on lipopolysaccharide-induced acute lung injury.
Respir Physiol Neurobiol. 2010; 170(3):253-9 [PubMed
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The aim of the present study was to evaluate the effects of the CC chemokine receptor (CCR) 2b and CCR1 antagonist RS504393 as well as the roles of CCRs on lipopolysaccharide (LPS)-induced acute lung injury (ALI). In A549 cell line, treatment with RS504393 significantly inhibited the expression of CCR1, CCR2 and interleukin (IL)-8 after either LPS or tumor necrosis factor-alpha stimulation. An ALI model with intranasal LPS administration was used on C57BL/6J, CCR1, CCR2 and CCR3 knockout mice. Treatment with RS504393 had a noteworthy preventative effect on LPS-induced over-expression of IL-1beta, plasminogen activator inhibitor and CCR2. In CCR1 and CCR2-deficient animals, LPS-induced less increase of lung weight, bronchoalveolar lavage (BAL) leukocytes and IL-6 compared to the C57BL/6J and CCR3 knockout mice. This was most prominent in the CCR2 knockout mice where no LPS-induced lung edema and no increase of IL-6 in BAL fluid occurred. Our results indicate that CCR2, and to some extent CCR1, play pivotal roles in the development of ALI.
BACKGROUND: It has been recognized cancer cells acquire characters reminiscent of those of normal stem cells, and the degree of stem cell gene expression correlates with patient prognosis. Lgr5(+) or CD133(+) epithelial stem cells (EpiSCs) have recently been identified and these cells are susceptible to neoplastic transformation. It is unclear, however, whether genes enriched in EpiSCs also contribute in tumor malignancy. Endometrial endometrioid carcinoma (EEC) is a dominant type of the endometrial cancers and is still among the most common female cancers. Clinically endometrial carcinoma is classified into 4 FIGO stages by the degree of tumor invasion and metastasis, and the survival rate is low in patients with higher stages of tumors. Identifying genes shared between advanced tumors and stem cells will not only unmask the mechanisms of tumor malignancy but also provide novel therapeutic targets.
RESULTS: To identify EpiSC genes in late (stages III-IV) EECs, a molecular signature distinguishing early (stages I-II) and late EECs was first identified to delineate late EECs at the genomics level. ERBB2 and CCR1 were genes activated in late EECs, while APBA2 (MINT2) and CDK inhibitor p16 tumor suppressors in early EECs. MAPK pathway was significantly up in late EECs, indicating drugs targeting this canonical pathway might be useful for treating advanced EECs. A six-gene mini-signature was further identified to differentiate early from advanced EECs in both the training and testing datasets. Advanced, invasive EECs possessed a clear EpiSC gene expression pattern, explaining partly why these tumors are more malignant.
CONCLUSIONS: Our work provides new insights into the pathogenesis of EECs and reveals a previously unknown link between adult stem cells and the histopathological traits of EECs. Shared EpiSC genes in late EECs may contribute to the stem cell-like phenotypes shown by advanced tumors and hold the potential of being candidate therapeutic targets and novel prognosis biomarkers.
Jung DW, Che ZM, Kim J, et al.Tumor-stromal crosstalk in invasion of oral squamous cell carcinoma: a pivotal role of CCL7.
Int J Cancer. 2010; 127(2):332-44 [PubMed
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Recent studies have shown that stromal fibroblasts have a more profound influence on the initiation and progression of carcinoma than was previously appreciated. This study aimed at investigating the reciprocal relationship between cancer cells and their associated fibroblasts at both the molecular and cellular level in oral squamous cell carcinoma (OSCC). To identify key molecular regulators expressed by carcinoma-associated fibroblasts (CAF) that promote cancer cell invasion, microarrays were performed by comparing cocultured OSCC cells and CAF with monoculture controls. Microarray and real-time PCR analysis identified marked upregulation of the chemokine (C-C motif) ligand 7 (CCL7) in cocultured CAF. ELISA showed an elevated level of CCL7 secretion from CAF stimulated by coculture with OSCC cells. CCL7 promoted the invasion and migration of OSCC cells, and the invasiveness was inhibited by treatment with CCL7 neutralizing antibody. OSCC cells were shown to express CCR1, CCR2 and CCR3, receptors for CCL7, by RT-PCR. In addition, treatment with anti-CCR1 or anti-CCR3 antibody inhibited CCL7-induced OSCC cell migration, implicating that CCL7 promotes cancer cell migration through CCR1 and CCR3 on OSCC cells. Cytokine antibody array analysis of the supernatant from OSCC cell culture revealed that interleukin-1alpha was an inducer of CCL7 secretion by CAF. This study confirms the reciprocal relationship of the molecular crosstalk regulating the invasion of OSCC and describes new potential targets for future therapy.
BACKGROUND: Therapeutic strategies exist for human pulmonary neoplasia, however due to the heterogeneity of the disease, most are not very effective. The innate immunity gene, toll-like receptor 4 (TLR4), protects against chronic pulmonary inflammation and tumorigenesis in mice, but the mechanism is unclear. This study was designed to identify TLR4-mediated gene expression pathways that may be used as prognostic indicators of susceptibility to lung tumorigenesis in mice and provide insight into the mechanism.
METHODS: Whole lung mRNA was isolated from C.C3H-Tlr4(Lps-d) (BALB(Lps-d); Tlr4 mutant) and BALB/c (Tlr4 normal) mice following butylated hydroxytoluene (BHT)-treatment (four weekly ip. injections; 150-200 mg/kg/each; "promotion"). mRNA from micro-dissected tumors (adenomas) and adjacent uninvolved tissue from both strains were also compared 27 wks after a single carcinogen injection (3-methylcholanthrene (MCA), 10 microg/g; "control") or followed by BHT (6 weekly ip. injections; 125-200 mg/kg/each; "progression"). Bronchoalveolar lavage fluid was analyzed for inflammatory cell content and total protein determination, a marker of lung hyperpermeability; inflammation was also assessed using immunohistochemical staining for macrophages (F4/80) and lymphocytes (CD3) in mice bearing tumors (progression).
RESULTS: During promotion, the majority of genes identified in the BALB(Lps-d) compared to BALB/c mice (P < 0.05) were involved in epithelial growth factor receptor (EGFR) signaling (e.g. epiregulin (Ereg)), secreted phosphoprotein 1(Spp1)), which can lead to cell growth and eventual tumor development. Inflammation was significantly higher in BALB(Lps-d) compared to BALB/c mice during progression, similar to the observed response during tumor promotion in these strains. Increases in genes involved in signaling through the EGFR pathway (e.g. Ereg, Spp1) were also observed during progression in addition to continued inflammation, chemotactic, and immune response gene expression in the BALB(Lps-d) versus BALB/c mice (P < 0.05), which appears to provide more favorable conditions for cell growth and tumor development. In support of these findings, the BALB/c mice also had significantly reduced expression of many immune response and inflammatory genes in both the tumors and uninvolved tissue.
CONCLUSION: This transcriptomic study determined the protective effect of TLR4 in lung carcinogenesis inhibition of multiple pathways including EGFR (e.g. Ereg), inflammatory response genes (e.g. Cxcl5), chemotaxis (e.g. Ccr1) and other cell proliferation genes (e.g. Arg1, Pthlh). Future studies will determine the utility of these pathways as indicators of immune system deficiencies and tumorigenesis.
Erreni M, Bianchi P, Laghi L, et al.Expression of chemokines and chemokine receptors in human colon cancer.
Methods Enzymol. 2009; 460:105-21 [PubMed
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Human colorectal cancer (CRC), the second largest cause of tumor-related death in Western countries, represents a paradigm for the now well-established connections between inflammation and cancer. In this study, we investigated which inflammatory mediators are mostly expressed in the microenvironment of human CRC. The RNA profile of a large panel of inflammatory genes, in particular chemokines and chemokine receptors, was analyzed in eight surgical tumor samples and in paired normal tissues from CRC patients. We employed an "inflammatory gene card" (TaqMan Low Density Array by Applied Biosystem), designed by our group, containing probes for 24 chemokines and 17 chemokine receptors. Several chemokines were strongly upregulated in the tumor microenvironment, most frequently CCL4 and CCL5, chemotactic for monocytes/macrophages and T cells, and the corresponding receptors CCR1 and CCR5; the angiogenic chemokines CXCL1 and CXCL8, and the receptor CXCR2. The antiangiogenic chemokines CXCL9 and CXCL10 were also expressed, but in the absence of the receptor CXCR3. Selected results have been confirmed in a larger number of samples. The levels of mRNA CXCL8 were significantly associated with the levels of osteopontin, a matrix-associated protein that shares with chemokines important functions such as induction of cell migration and survival, and modulation of the neoangiogenesis. Overall these results could be helpful to identify the most relevant inflammatory pathways present in CRC tumors and to build a solid rationale for future therapeutic interventions based on anti-inflammatory strategies.
Zucchetto A, Benedetti D, Tripodo C, et al.CD38/CD31, the CCL3 and CCL4 chemokines, and CD49d/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival.
Cancer Res. 2009; 69(9):4001-9 [PubMed
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CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38(+)CD49d(+) versus CD38(-)CD49d(-) CLL cells, we showed overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also up-regulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38(+)CD49d(+) but not CD38(-)CD49d(-) cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68(+) macrophage infiltration was particularly high in BMB from CD38(+)CD49d(+) CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express vascular cell adhesion molecule-1 (VCAM-1), the CD49d ligand, likely through tumor necrosis factor alpha overproduction. These effects were apparent in BMB from CD38(+)CD49d(+) CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1(+) stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1 transfectants increased viability of CD38(+)CD49d(+) CLL cells. Altogether, CD38 and CD49d can be thought of as parts of a consecutive chain of events ultimately leading to improved survival of CLL cells.
Chuang JY, Yang WH, Chen HT, et al.CCL5/CCR5 axis promotes the motility of human oral cancer cells.
J Cell Physiol. 2009; 220(2):418-26 [PubMed
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CCL5 (previously called RANTES) is in the CC-chemokine family and plays a crucial role in the migration and metastasis of human cancer cells. On the other hand, the effect of CCL5 is mediated via CCR receptor. RT-PCR and flow cytometry studies demonstrated CCR5 but not CCR1 and CCR3 mRNA in oral cancer cell lines, especially higher in those with high invasiveness (SCC4) as compared with lower levels in HSC3 cells and SCC9 cells. Stimulation of oral cancer cells with CCL5 directly increased the migration and metalloproteinase-9 (MMP-9) production. MMP-9 small interfering RNA inhibited the CCL5-induced MMP-9 expression and thereby significantly inhibited the CCL5-induced cell migration. Activations of phospholipase C (PLC), protein kinase Cdelta (PKCdelta), and NF-kappaB pathways after CCL5 treatment was demonstrated, and CCL5-induced expression of MMP-9 and migration activity was inhibited by the specific inhibitor of PLC, PKCdelta, and NF-kappaB cascades. In addition, migration-prone sublines demonstrate that cells with increasing migration ability had more expression of MMP-9, CCL5, and CCR5. Taken together, these results indicate that CCL5/CCR5 axis enhanced migration of oral cancer cells through the increase of MMP-9 production.
Iwakiri S, Mino N, Takahashi T, et al.Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer.
Cancer. 2009; 115(11):2580-93 [PubMed
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BACKGROUND: The authors elucidated particular chemokine receptors that are expressed on lung cancer cells, as well as the clinical significance of the expression of these chemokine receptors in completely resected nonsmall cell lung cancer (NSCLC).
METHODS: The authors examined gene expression of chemokine receptors (CCR1-11, CXCR1-7, XCR1, and CX3CR1) in 11 cell lines of lung cancer, and gene expression of CXCR3, CXCR4, and CXCR7 (CXCR3/4/7) in surgical specimens of 127 patients who underwent complete resection for their NSCLC between May 2001 and December 2002, using quantitative real-time reverse transcriptase-polymerase chain reaction (PCR). Mutation detection analysis of the EGFR genes using the PCR single-strand conformational polymorphism method was evaluated in patients with pathological (p-) stage I adenocarcinoma.
RESULTS: Substantial expression of CXCR3/4/7 mRNA was observed in all NSCLC cell lines examined. In p-stage I NSCLC, CXCR4 and CXCR7 expression values in patients with postoperative metastatic recurrence (Rec-Distant) were significantly higher than in those without recurrences (P = .003 and P = .007, respectively). In addition, the 5-year disease-free survival (DFS) rate of high CXCR7-expressing patients (63.2%) was significantly lower than that of low CXCR7-expressing patients (84.8%) (P = .033). The EGFR mutation was significantly more frequent in patients with higher CXCR7 expression (14 of 21 patients) than in those with lower CXCR7 expression (12 of 32 patients) (P = .038). A multivariate analysis confirmed that high CXCR7 expression was an independent and significant factor predicting a poor DFS in p-stage I NSCLC patients (P = .041).
CONCLUSIONS: Higher expression of CXCR7 is associated with Rec-Distant and poor DFS in patients with p-stage I NSCLC.
Fukada SY, Silva TA, Garlet GP, et al.Factors involved in the T helper type 1 and type 2 cell commitment and osteoclast regulation in inflammatory apical diseases.
Oral Microbiol Immunol. 2009; 24(1):25-31 [PubMed
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INTRODUCTION: Periapical chronic lesion formation involves activation of the immune response and alveolar bone resorption around the tooth apex. However, the overall roles of T helper type 1 (Th1), Th2, and T-regulatory cell (Treg) responses and osteoclast regulatory factors in periapical cysts and granulomas have not been fully determined. This study aimed to investigate whether different forms of apical periodontitis, namely cysts and granulomas, show different balances of Th1, Th2 regulators, Treg markers, and factors involved in osteoclast chemotaxis and activation.
METHODS: Gene expression of these factors was assessed using quantitative real-time polymerase chain reaction, in samples obtained from healthy gingiva (n = 8), periapical granulomas (n = 20), and cysts (n = 10).
RESULTS: Periapical cysts exhibited a greater expression of GATA-3, while a greater expression of T-bet, Foxp3, and interleukin-10 (IL-10) was seen in granulomas. The expression of interferon-gamma, IL-4, and transforming growth factor-beta was similar in both lesions. Regarding osteoclastic factors, while the expression of SDF-1alpha/CXCL12 and CCR1 was higher in cysts, the expression of RANKL was significantly higher in granulomas. Both lesions exhibited similar expression of CXCR4, CKbeta8/CCL23, and osteoprotegerin, which were significantly higher than in control.
CONCLUSION: Our results showed a predominance of osteoclast activity in granulomas that was correlated with the Th1 response. The concomitant expression of Treg cell markers suggests a possible suppression of the Th1 response in granulomas. On the other hand, in cysts the Th2 activity is augmented. The mechanisms of periradicular lesion development are still not fully understood but the imbalance of immune and osteoclastic cell activity in cysts and granulomas seems to be critically regulated by Treg cells.
Allam MM, Abd El Moneim E, Hassouna MM, et al.Levels of chemokine receptors expressed on peripheral blood T lymphocytes of Egyptian patients with hepatocellular carcinoma.
Egypt J Immunol. 2009; 16(1):17-25 [PubMed
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CC chemokine receptors (CCR) have an important role in the recruitment of leukocytes to the site of inflammation. The migration and metastasis of tumor cells shares many similarities with leukocyte trafficking, which is mainly regulated by chemokine receptor-ligand interactions. CCR1 and CCR5 are highly expressed in hepatocellular carcinoma (HCC) cells and tissues with unknown functions. In this study, we estimated the surface expression of chemokine receptors CCR1 and CCR5 on the lymphocytes of peripheral blood from patients with HCC in an attempt to identify their roles in tumorigenesis. The study was conducted on 52 patients of which, 24 of them with confirmed HCC and 28 with chronic hepatitis C virus infection. In addition, 20 apparently healthy controls with matched age and sex were also included in the study. All patient and control groups were subjected to the following: thorough history taking, clinical examination, abdominal ultrasonography and fine needle liver biopsy for patient's group when needed, complete blood count, liver function tests, viral markers for hepatitis B and C, serum alpha fetoprotein and flowcytometric detection of chemokine receptors CCR1 and CCR5 on peripheral blood T lymphocytes. The expression of chemokine receptors CCR1 and CCR5 on CD4+ and CD8+ T lymphocytes was significantly less in HCC and hepatitis C patient groups as compared to control group. Moreover, a significant decrease in the levels of CCR1 and CCR5 on CD8+ T lymphocytes was detected in HCC patients compared to patients with chronic HCV; however, it was not statistically significant for CD4+ cells. Furthermore in HCC patients, levels of CCR1 and CCR5 were significantly less in patients with large tumor size than small sized tumor. Data obtained showing reduced surface expression of CCR1 and CCR5 on CD4 and CD8 T lymphocytes reflect their possible role in altering the host's immune defense and disease pathogenesis, thus may be helpful for therapy design to ameliorate disease progression.
Lee S, Kang J, Cho M, et al.Profiling of transcripts and proteins modulated by K-ras oncogene in the lung tissues of K-ras transgenic mice by omics approaches.
Int J Oncol. 2009; 34(1):161-72 [PubMed
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The mutated K-ras gene is involved in approximately 30% of human cancers. In order to search for K-ras oncogene-induced modulators in lung tissues of K-ras transgenic mice, we performed microarray and proteomics (LC/ESI-MS/MS) analysis. Genes (RAB27b RAS family, IL-1RA, IL-33, chemokine ligand 6, epiregulin, EGF-like domain and cathepsin) related to cancer development (Wnt signaling pathway) and inflammation (chemokine/cytokine signaling pathway, Toll receptor signaling) were up-regulated while genes (troponin, tropomodulin 2, endothelial lipase, FGFR4, integrin alpha8 and adenylate cyclase 8) related to the tumor suppression such as p53 pathway, TGF-beta signaling pathway and cadherin signaling pathway were down-regulated by K-ras oncogene. Proteomics approach revealed that up-regulated proteins in lung adenomas of K-ras mice were classified as follows: proteins related to the metabolism/catabolism (increased from 7 to 22% by K-ras gene), proteins related to translation/transcription and nucleotide (from 4 to 6%), proteins related to signal transduction (from 3 to 5%), proteins related to phosphorylation (from 1 to 2%). ATP synthase, Ras oncogene family, cytochrome c oxidase, flavoprotein, TEF 1, adipoprotein A-1 BP, glutathione oxidase, fatty acid BP 4, diaphorase 1, MAPK4 and transgelin were up-regulated by K-ras oncogene. However, integrin alpha1, Ras-interacting protein (Rain), endothelin-converting enzyme-1d and splicing factor 3b were down-regulated. These studies suggest that genes related to cancer development and inflammation were up-regulated while genes related to the tumor suppression were down-regulated by K-ras, resulting in the tumor growth. Putative biomarkers such as cell cycle related genes (Cdc37), cancer cell adhesion (Glycam 1, integrin alpha8, integrin alphaX and Clec4n), signal transduction (Tlr2, IL-33, and Ccbp2), migration (Ccr1, Ccl6, and diaphorase 1 (Cyb5r3) and cancer development (epiregulin) can be useful for diagnosis and as prognosis markers and some of the target molecules can be applied for prevention of cancer.
Wang CL, Sun BS, Tang Y, et al.CCR1 knockdown suppresses human non-small cell lung cancer cell invasion.
J Cancer Res Clin Oncol. 2009; 135(5):695-701 [PubMed
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PURPOSE: CC chemokine receptor 1 (CCR1) plays a critical role in the recruitment of leukocytes to the site of inflammation. Tumor invasion and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. In this study, we aimed to assess the role of CCR1 in non-small cell lung cancer (NSCLC).
METHODS: CCR1 expression was determined by Western blotting in two human NSCLC clones (95C and 95D) with different metastatic potential. We silenced CCR1 expression through microRNA-mediated RNA interference, and examined the invasiveness and proliferation of CCR1-silenced NSCLC cell through Matrigel assay and MTT assay. Matrix metalloproteinases (MMPs) activity was determined by gelatin zymography.
RESULTS: We found that expression of CCR1 was correlated with the aggressive phenotype of the NSCLC cells. CCR1 knockdown significantly suppressed the invasiveness of NSCLC cells, but had only a minor effect on cell proliferation. Moreover, we demonstrated that CCR1 knockdown significantly reduced the expression level of matrix metalloproteinase-9.
CONCLUSIONS: These findings suggest that CCR1 contributes to NSCLC cell migration by stimulating cell invasion, independent of cell proliferation. CCR1 might be a new target for NSCLC therapy.
Kominsky SL, Abdelmagid SM, Doucet M, et al.Macrophage inflammatory protein-1 delta: a novel osteoclast stimulating factor secreted by renal cell carcinoma bone metastasis.
Cancer Res. 2008; 68(5):1261-6 [PubMed
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Approximately 30% of patients with renal cell carcinoma (RCC) develop bone metastasis, which is characterized by extensive osteolysis leading to severe bone pain and pathologic fracture. Although the mechanism of RCC-induced osteolysis is unknown, studies of bone metastasis have shown that tumor-induced changes in bone remodeling are likely mediated by alterations in the bone microenvironment. Here, we report the discovery of a novel osteoclast stimulatory factor secreted by RCC bone metastasis (RBM). Through microarray analysis, we found expression of the chemokine, macrophage inflammatory protein-1 delta (MIP-1 delta), to be increased in RBM versus patient-matched primary RCC tissues and confirmed this finding by quantitative reverse transcription-PCR (qRT-PCR) and ELISA (P < 0.05). Furthermore, MIP-1 delta expression in RBM tissues was significantly (P < 0.001) higher than in human bone marrow, suggesting a potential alteration of the bone microenvironment. The receptors for MIP-1 delta, CCR1 and CCR3, were expressed in both osteoclast precursors and mature, bone-resorbing osteoclasts as shown by qRT-PCR and Western analysis. In functional studies, MIP-1 delta stimulated chemotaxis of two osteoclast precursor cell types: murine bone marrow mononuclear cells (BM-MNC) and RAW 264.7 cells. Furthermore, MIP-1 delta treatment of murine calvaria caused increased bone resorption as determined by measurement of released calcium. Correspondingly, MIP-1 delta significantly enhanced osteoclast formation and activity in response to RANKL in both BM-MNC and RAW 264.7 cells. Taken together, these data suggest that MIP-1 delta expression is increased in RBM relative to RCC and bone marrow, and may promote RBM-induced osteolysis by stimulating the recruitment and differentiation of osteoclast precursors into mature osteoclasts.
BACKGROUND: Osteosarcoma is the most frequent bone tumor in childhood and adolescence. Patients with primary metastatic disease have a poor prognosis. It is therefore important to better characterize the biology of this tumor to define new prognostic markers or therapeutic targets for tailored therapy. Chemokines and their receptors have been shown to be involved in the development and progression of malignant tumors. They are thought to be active participants in the biology of osteosarcoma. The function of specific chemokines and their receptors is strongly associated with the biological context and microenvironment of their expression. In this report we characterized the expression of a series of chemokine receptors in the complex environment that defines osteosarcoma.
METHODS: The overall level of chemokine receptor mRNA expression was determined using TaqMan RT-PCR of microdissected archival patient biopsy samples. Expression was then verified at the protein level by immunohistochemistry using a series of receptor specific antibody reagents to elucidate the cellular association of expression.
RESULTS: Expression at the RNA level was found for most of the tested receptors. CCR1 expression was found on infiltrating mononuclear and polynuclear giant cells in the tumor. Cells associated with the lining of intratumoral vessels were shown to express CCR4. Infiltrating mononuclear cells and tumor cells both showed expression of the receptor CCR5, while CCR7 was predominantly expressed by the mononuclear infiltrate. CCR10 was only very rarely detected in few scattered infiltrating cells.
CONCLUSION: Our data elucidate for the first time the cellular context of chemokine receptor expression in osteosarcoma. This is an important issue for better understanding potential chemokine/chemokine receptor function in the complex biologic processes that underlie the development and progression of osteosarcoma. Our data support the suggested involvement of chemokines and their receptors in diverse aspects of the biology of osteosarcoma, but also contradict aspects of previous reports describing the expression of these receptors in this tumor.
Byers RJ, Sakhinia E, Joseph P, et al.Clinical quantitation of immune signature in follicular lymphoma by RT-PCR-based gene expression profiling.
Blood. 2008; 111(9):4764-70 [PubMed
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Microarray gene expression profiling studies have demonstrated immune response gene signatures that appear predictive of outcome in follicular lymphoma (FL). However, measurement of these marker genes in routine practice remains difficult. We have therefore investigated the immune response in FL using real-time polymerase chain reaction (PCR) to measure expression levels of 35 candidate Indicator genes, selected from microarray studies, to polyA cDNAs prepared from 60 archived human frozen lymph nodes, in parallel with immunohistochemical analysis for CD3, CD4, CD7, CD8, CD10, CD20, CD21, and CD68. High levels of CCR1, a marker of monocyte activation, were associated with a shorter survival interval, and high levels of CD3 with better survival, while immunohistochemistry demonstrated association of high numbers of CD68(+) macrophages with a shorter survival interval and of high numbers of CD7(+) T cells with a longer survival interval. The results confirm the role of the host immune response in outcome in FL and identify CCR1 as a prognostic indicator and marker of an immune switch between macrophages and a T cell-dominant response. They demonstrate the utility of polyA DNA and real-time PCR for measurement of gene signatures and the applicability of using this type of "molecular block" in clinical practice.
Freedman RS, Ma Q, Wang E, et al.Migration deficit in monocyte-macrophages in human ovarian cancer.
Cancer Immunol Immunother. 2008; 57(5):635-45 [PubMed
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PURPOSE: 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.