Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocyte chemotactic protein-1 (MCP-1, CCL2) is an important determinant of macrophage infiltration in tumors, ovarian carcinoma in particular. MCP-1 binds the chemokine receptor CCR2. Recent results indicate that proinflammatory and anti-inflammatory signals regulate chemokine receptor expression in monocytes. The present study was designed to investigate the expression of CCR2 in tumor-associated macrophages (TAM) from ovarian cancer patients. TAM isolated from ascitic or solid ovarian carcinoma displayed defective CCR2 mRNA (Northern blot and PCR) and surface expression and did not migrate in response to MCP-1. The defect was selective for CCR2 in that CCR1 and CCR5 were expressed normally in TAM. CCR2 gene expression and chemotactic response to MCP-1 were decreased to a lesser extent in blood monocytes from cancer patients. CCR2 mRNA levels and the chemotactic response to MCP-1 were drastically reduced in fresh monocytes cultured in the presence of tumor ascites from cancer patients. Ab against TNF-alpha restored the CCR2 mRNA level in monocytes cultured in the presence of ascitic fluid. The finding of defective CCR2 expression in TAM, largely dependent on local TNF production, is consistent with previous in vitro data on down-regulation of chemokine receptors by proinflammatory molecules. Receptor inhibition may serve as a mechanism to arrest and retain recruited macrophages and to prevent chemokine scavenging by mononuclear phagocytes at sites of inflammation and tumor growth. In the presence of advanced tumors or chronic inflammation, systemic down-regulation of receptor expression by proinflammatory molecules leaking in the systemic circulation may account for defective chemotaxis and a defective capacity to mount inflammatory responses associated with advanced neoplasia.
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PMID:Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with human ovarian carcinoma. 1062 17

Using flow cytometric and RNase protection assays, this study examined the expression of chemokine receptors in nonactivated natural killer (NK) cells and compared this expression with NK cells activated with interleukin (IL)-2, which either adhered to plastic flasks (AD) or did not adhere (NA). None of the NK cell subsets expressed CXCR2, CXCR5, or CCR5. The major differences between these cells include increased expression of CXCR1, CCR1, CCR2, CCR4, CCR8, and CX(3)CR1 in AD when compared to NA or nonactivated NK cells. The chemotactic response to the CXC and CC chemokines correlated with the receptor expression except that all 3 populations responded to GRO-alpha, despite their lack of CXCR2 expression. Pretreatment of these cells with anti-CXCR2 did not inhibit the chemotactic response to GRO-alpha. In addition, nonactivated and NA cells responded to fractalkine, although they lack the expression of CX(3)CR1. This activity was not inhibited by anti-CX(3)CR1. Viral macrophage inflammatory protein (vMIP)-I, I-309, and TARC competed with the binding of (125)I-309 to AD cells with varying affinities. Transforming growth factor (TGF)-beta1 but not any other cytokine or chemokine examined including interferon (IFN)-gamma, MIP-3beta, macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC) or I-309, up-regulated the expression of CXCR3 and CXCR4 on NK cell surface. This is correlated with increased chemotaxis of NK cells treated with TGF-beta1 toward stromal cell-derived factor (SDF)-1alpha and interferon-inducible protein-10 (IP-10). Messenger RNA for lymphotactin, RANTES, MIP-1alpha, and MIP-1beta, but not IP-10, monocyte chemotactic protein (MCP)-1, IL-8, or I-309 was expressed in all 3 NK cell subsets. Our results may have implications for the dissemination of NK cells at the sites of tumor growth or viral replication. (Blood. 2001;97:367-375)
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PMID:Expression and regulation of chemokine receptors in human natural killer cells. 1115 10

We have previously shown that inoculation of human chromosome 3 (chr3)/A9 mouse fibrosarcoma microcell hybrids (MCHs) into severe combined immunodeficient (SCID) mice was followed by the regular elimination of some 3p regions whereas a 3q region was retained even after prolonged mouse passage. Using this approach, referred to as the elimination test (Et), we have defined a common eliminated region (CER) of approximately 7 cM at 3p21.3 that was absent in all of the 27 tumors generated from five MCHs. Later, CER was reduced to a 1-Mb region, designated as CER1. Another eliminated region (ER2) at 3p21.1-p14.2 was absent in 21 of the 27 tumors. ER2 borders at but does not include the fragile histidine triad (FHIT) gene, considered as a putative tumor suppressor gene. In the present work, two new and two previously studied MCHs, and 13 derived SCID mouse tumors were analyzed by fluorescence in situ hybridization (FISH) chromosome painting and by PCR, using 72 chr3p-specific and 11 chr3q-specific markers. Nine tumors generated from three MCHs that carried cytogenetically normal chr3, remained PCR-positive for all of the chr3 markers tested. Designated as "PCR+" tumors, they were examined by reverse transcription (RT)-PCR, together with four of six previously studied tumors derived from MCH910.7, which carried a del(3)(pter-p21.1), for the expression of 14 human genes: 5 genes within CER1 (LIMD1, CCR1, CCR2, CCR3, CCR5), 5 genes located within regions that were homozygously deleted in a variety of carcinomas (ITGA4L, LUCA1, PTPRG, FHIT, DUTT1), and 4 other genes in chr3p (VHL, MLH1, TGM4, UBE1L). We found that VHL, MLH1, ITGA4L, LIMD1, UBE1L, LUCA1, PTPRG, and DUTT1 were expressed in the MCH lines in vitro and also in the derived SCID tumors. No transcripts that originated from the four CCR genes or from TGM4 could be detected in any of the MCH lines. Alone among the 14 genes examined, FHIT showed a tumor growth-associated change. It was expressed in vitro in five of seven MCH lines. Nine of 13 derived tumors had no FHIT transcript. The remaining 4 expressed a truncated mRNA and a reduced amount of the full-length mRNA. We have previously found that FHIT was deleted at the DNA level in 17 of 21 tumors derived from four MCHs. The remaining 4 of 21 had no FHIT transcript. Our compiled data show that FHIT was either physically or functionally impaired in all 34 of the 34 analyzed tumors. Variants with deleted or down-regulated FHIT have a selective growth advantage.
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PMID:Inactivation of the human fragile histidine triad gene at 3p14.2 in monochromosomal human/mouse microcell hybrid-derived severe combined immunodeficient mouse tumors. 1115 20

The immune system attempts to prevent or limit tumor growth, yet efforts to induce responses to tumors yield minimal results, rendering tumors virtually invisible to the immune system [1]. Several mechanisms may account for this subversion, including the triggering of tolerance to tumor antigens [2, 3], TGF-alpha or IL-10 production, downregulation of MHC molecules, or upregulation of FasL expression [4, 5]. Melanoma cells may in some instances use FasL expression to protect themselves against tumor-infiltrating lymphocytes (TIL) [4, 5]. Here, we show another, chemokine-dependent mechanism by which melanoma tumor cells shield themselves from immune reactions. Melanoma-inducible CCL5 (RANTES) production by infiltrating CD8 cells activates an apoptotic pathway in TIL involving cytochrome c release into the cytosol and activation of caspase-9 and -3. This process, triggered by CCL5 binding to CCR5, is not mediated by TNFalpha, Fas, or caspase-8. The effect is not unique to CCL5, as other CCR5 ligands such as CCL3 (MIP-1alpha) and CCL4 (MIP-1beta) also trigger TIL cell death, nor is it limited to melanoma cells, as it also operates in activated primary T lymphocytes. The model assigns a role to the CXC chemokine CXCL12 (SDF-1alpha) in this process, as this melanoma cell-produced chemokine upregulates CCL5 production by TIL, initiating TIL cell death.
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PMID:A potential immune escape mechanism by melanoma cells through the activation of chemokine-induced T cell death. 1136 32

Previous work has shown that dendritic cells (DCs) express specific chemokine receptors that allow for coordinated movement in vivo. To test the in vivo relevance of this, we used a murine melanoma system and knockout mice to investigate the function of the chemokine receptor CCR5 and its ligands, CCR ligand (CCL)3 and CCL5. We found that the lack of CCR5 in the host mouse resulted in delayed tumor growth, but this effect was overcome at a higher tumor load. With the administration of tumor charged DCs, CCR5(-/-) mice that had previously been injected with tumor were completely protected from tumor. This effect was dependent on the dose of tumor cells and the expression of CCR5 on the DC and its absence in the host. In contrast, the loss of the CCR5 ligand, CCL3, led to an early delay in tumor growth that did not persist, while the absence of the CCR5 ligand, CCL5, had no effect. Blocking the activity of CCR5 in the host may represent a new strategy for enhancing the activity of a therapeutic melanoma DC vaccine.
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PMID:Host absence of CCR5 potentiates dendritic cell vaccination. 1268 53

Chemokines are pro-inflammatory cytokines that function to attract immune cells to the sites of tissue inflammation, injury or infection. We have formulated the hypothesis that release of one chemokine can serve, in a local paracrine or endocrine fashion, to induce the release of other chemokines from neighboring mammary cells. We set out to investigate whether specific chemokines could promote the release of other chemokine members from mammary cells, and whether estrogen could serve to disrupt the release of these chemokines from mammary cells. We found that treatment with the chemokine IP-10 resulted in significant increases in the amount of MIP-1alpha and MCP-1/JE released from murine mammary cells. Estrogen co-treatment significantly blocked the ability of IP-10 to trigger the release of MIP-1alpha and MCP-1/JE. Suppressive effects of estrogen were reversed upon co-treatment with 4-hydroxytamoxifen. Estrogen treatment significantly decreased expression of proteins corresponding to the chemokine receptors CXCR3 and CCR5 on mammary cells. Exposure of female mice to IP-10 in vivo significantly decreased the ability of estrogen to support the growth of CCL-51-based tumors in mammary tissue. Our results suggest that exposure of mammary tissue to estrogen may decrease the release of local chemokines from mammary cells, potentially increasing the risk of tumor growth through decreased immune surveillance. Ongoing studies are investigating the possible mechanisms through which IP-10 stimulates the release of chemokines from mammary cells, and how the action of IP-10 may serve to decrease mammary tumor formation.
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PMID:Estrogen disrupts chemokine-mediated chemokine release from mammary cells: implications for the interplay between estrogen and IP-10 in the regulation of mammary tumor formation. 1502 21

Chemokines participate in the antitumor immune response by regulating the movement and positioning of lymphocytes as well as effector functions and may thus be candidates for use in antitumor therapy. To test whether CCL5, a chemokine involved in the recruitment of a wide spectrum of immunocompetent cells, can control tumor growth, we forced its expression at mouse tumor sites. Tumor growth was reduced in mice with s.c. syngeneic CCL5-EL-4 compared with EL-4-injected mice, whereas both reduced tumor growth and incidence were observed in mice with OVA-expressing EG-7 transfected with CCL5 compared with EG-7-injected mice. Significant antitumor effects were observed soon after intratumoral injection of DNA plasmid coding for chimeric CCL5-Ig. Importantly, quantitative RT-PCR assays showed that the amount of CCL5 expression at the tumor site determined the effectiveness of the antitumor response, which was associated with infiltration of increased numbers of NK, CD4, and CD8 cells at the tumor site. This effect was lost in mice deficient for T/B lymphocytes (RAG-2 knockout) or for CCR5 (CCR5 knockout). Together, these data demonstrate the antitumor activity of intratumoral CCL5 overexpression, due to its recruitment of immunocompetent cells, and the potential usefulness of chimeric CCL5-Ig DNA as an agent in cancer therapy.
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PMID:Intratumoral CC chemokine ligand 5 overexpression delays tumor growth and increases tumor cell infiltration. 1535 22

Recent data suggest that chemokines and chemokine receptors mediate leukocyte recruitment of all components of the antitumor response. This study aimed to phenotypically characterize the immune lymphocyte infiltrate in human renal cell carcinomas RCCs and at the invasive margin (tumor-host interface) and to define the association of these findings with established prognostic indicators. Tumor infiltrating lymphocytes TILs were obtained from 24 patients with RCC undergoing radical nephrectomy. Peripheral blood cells from 37 patients were also obtained before surgery. Our findings are consistent with the preferential recruitment of CD4+ Th1-polarized effector memory cells that express CXCR3/CCR5. These cells were the main component of TILs and expressed as CXCR3, CCR5, CD45RO, and CD95. Natural killer (NK) cells were found in significantly higher proportions in TILs of RCCs than in peripheral blood lymphocytes (PBLs) or in other tumors studied (colorectal and breast cancers), where these cells were found in small proportions. No differences in nuclear grade or other studied parameters were observed between the TILs and the lymphocytes present at the invasive margin, which showed a similar composition. However, differences were found according to the tumor stage. First, significantly fewer NK cells were observed in PBLs from metastatic patients. Second, a significantly lower proportion of CCR5/CXCR3/CD4+ cells and a higher proportion of CCR4/CD4+ cells were observed in metastatic patients, suggesting that preferential Th1-polarization may gradually change during the progression of renal cancer cells. Finally, the frequency of CD25/CD4+ cells was higher in metastatic patients. Although the sample of patients with metastasis was small, the overall results suggest a change in composition of the TILs that may potentially confer a selective advantage for tumor growth and may account for the suppression of an effective cytotoxic response.
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PMID:Analysis of NK cells and chemokine receptors in tumor infiltrating CD4 T lymphocytes in human renal carcinomas. 1588 15

The C-C chemokines, macrophage inflammatory protein (MIP)1alpha and MIP1beta are potent chemoattractants for the monocytes, which form an important component of the stroma of tumor tissue and may regulate tumor growth and associated inflammation. We examined the role of MIP1alpha and MIP1beta in inducing the release of inflammatory cytokines and the generation of tumoricidal monocytes from the peripheral blood monocytes (PBM) of healthy women and patients with carcinoma of breast (CaBr). Interleukin-1 (IL-1) and tumor necrosis factor (TNF) alpha release by the PBM was markedly stimulated by MIP1alpha in CaBr patients, but only marginally so in healthy women. In contrast, MIP1beta stimulated the release of these cytokines by the PBM of healthy women, but failed to do so in CaBr patients. MIP1alpha, but not MIP1beta, synergized with LPS in inducing the release of IL-1 from the PBM of both healthy women and CaBr patients. Both MIP1alpha and MIP1beta augmented respiratory bursts in PBM and generated tumoricidal PBM that killed T24 cells, MIP1alpha being more effective in CaBr patients and MIP1beta in healthy women. IFN-gamma co-stimulated and IL-4 suppressed MIP1alpha and beta-induced cytotoxicity in PBM. The synergy of IFN-gamma was more marked with MIP1alpha than with MIP1beta. The differential effects of MIP1alpha and MIP1beta on the PBM of healthy women and CaBr patients co-related with the levels of expression of CCR1 and CCR5 in these monocytes. The expression of CCR5 was higher than that of CCR1 in the PBM of healthy women and the PBM of the CaBr patients showed overexpression of CCR1 and downregulation of CCR5.
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PMID:Macrophage inflammatory protein (MIP)1alpha and MIP1beta differentially regulate release of inflammatory cytokines and generation of tumoricidal monocytes in malignancy. 1651 99

Chemokines are small chemotactic cytokines that can induce the migration of leukocytes, activate inflammatory/immune responses and have recently been implicated in the regulation of tumor growth and organ-specific spread. In this setting, the macrophage inflammatory protein-1alpha (CCL3) chemokine displays a diversity of roles that may contribute to the directional migration of squamous cells into cervical lymph nodes or to the defense against tumor initiation and progression. Thus, the aim of this study was to determine, for the first time, the expression of CCL3 and their receptors, CCR1 and CCR5, by real-time polymerase chain reaction in samples obtained from oral squamous cell carcinoma (OSCC) and healthy gingival tissue (control). In addition, we investigated the immunoexpression of these molecules in neoplastic cells (parenchyma), inflammatory/immune cells (stroma) in primary OSCC and in metastatic and non-metastatic lymph node tissues. The relationship of CCL3/CCR1 with survival data was also evaluated. The analysis of mRNA expression revealed a significantly higher expression of CCL3 and CCR1 in OSCC compared with the controls (P<0.05). The expression of CCR5 was not different in the two groups. The percentages of CCL3+ and CCR1+ cells were observed to be similar in parenchyma and stroma in the OSCC without lymph node metastasis when compared with OSCC with lymph node metastasis (P>0.05). However, we observed the density of CCL3+ nodal cells to be significantly higher in metastatic lymph nodes when compared with non-metastatic lymph nodes in the same patients (P<0.05). Considering CCL3 in stroma, the mean survival rate for patients with high CCL3+ cell percentage was better than for those with low CCL3+ cell percentage. Our findings suggest that the CCL3/CCR1 axis may have a role in the spread of tumoral cells to the lymph nodes and also in the local host defense against the tumor.
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PMID:Dual role of CCL3/CCR1 in oral squamous cell carcinoma: implications in tumor metastasis and local host defense. 1791 60


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