UMLS:C0677930 - FACTA Search

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Query: UMLS:C0677930 (primary tumor)
20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung cancer is the leading cause of malignancy-related mortality in the U.S. and is predicted to increase over the remainder of this decade. Despite attempts to advance early diagnosis and use combination therapies, the clinical response of this cancer yields an overall 5-year survival rate of less than 15%. Clearly, new strategies for therapy are indicated. Although carcinogenesis is complex, tumor growth beyond 1-2 mm3 is dependent on angiogenesis. One of the potential mechanisms that allows for tumorigenesis is dysregulation of the balance of angiogenic and angiostatic factors that favors net neovascularization within the primary tumor. Numerous studies have investigated the role of a variety of molecules in the regulation of angiogenesis. Recently, interleukin-8 (IL-8), a member of the C-X-C chemokine family, has been found to be an angiogenic factor. In contrast, platelet factor 4 (PF4), another C-X-C chemokine, has been shown to have angiostatic properties. It is interesting that the major structural difference between IL-8 and PF4 is the presence of the NH2-terminal ELR (Glu-Leu-Arg) motif that precedes the first cysteine amino acid residue of IL-8 and is important in ligand/receptor interactions. We hypothesize that angiogenesis associated with tumorigenesis is dependent on members of the C-X-C chemokine family acting as either angiogenic or angiostatic factors. This paradigm predicts that the biological balance in the expression of these C-X-C chemokines dictates whether the neoplasm grows and develops metastatic potential or regresses. In this review we discuss our recent laboratory findings that support this contention and suggest that further elucidation of the biology of C-X-C chemokines in the context of neovascularization of nonsmall cell lung cancer will permit novel targeted therapy aimed specifically at attenuating tumor growth and metastasis.
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PMID:Role of C-X-C chemokines as regulators of angiogenesis in lung cancer. 753 29

IIB-BR-G is an undifferentiated, highly heterogeneous, hormone receptor negative human breast cancer cell line previously established in our laboratory from a patient's primary tumor. An in vitro growing cell line (IIB-BR-G) and a xenotransplanted tumor growing in nude mice (IIB-BR-G(NUDE)) were derived. To further characterize these systems, immunocytochemical analysis was performed for differentiation antigens (PEM 200 kDa, CEA, NCA 90 kDa), blood-group related antigens (Le(x), sTn), oncogenes and tumor suppressor gene products (Her-2/neu protein, p53), metastasis-related cathepsin D and CD63/5.01 Ag, and the chemokine monocyte chemotactic protein 1 (MCP-1). Expression of markers was heterogeneous in these different systems. Previously reported karyotypic analysis has shown extensive chromosomal alterations including double min. Searching for oncogene amplification, we detected augmented copy number of c-myc and c-fos, the last one with two rearranged fragments. No amplification was found for c-erbB-2 in the cell line or in IIB-BR-G(NUDE), although this oncogene was amplified in the patient's primary tumor DNA. The differences observed between the patient's tumor, the cell line and the IIB-BR-G(NUDE) tumors are probably due to clonal expansion of cell variants not present in the original tumor. Electron microscopy of IIB-BR-G growing cells revealed epithelial characteristics with abundant dense granules, presumably secretory, distributed all over the cytoplasm and great nuclear pleomorphism. In vitro, IIB-BR-G cells showed a significant number of invading cells by Matrigel assay. After nearly 40 sequential subcutaneous passages of the original xenograft through nude mice, 80% of recipients developed spontaneous metastases, primarily to the lung and lymph nodes. Since this experimental model allowed to analyze changes produced in cancer cells from the primary tumor during adaptation to in vitro and in vivo growth, our results provide novel insights on the behaviour of hormone independent metastatic breast cancer.
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PMID:The human breast cancer cell line IIB-BR-G has amplified c-myc and c-fos oncogenes in vitro and is spontaneously metastatic in vivo. 962 Apr 46

The beta-chemokine RANTES was measured in plasma in 43 patients with breast cancer and in 23 patients with cervical cancer, and the RANTES content in primary tumors, tumor metastatic to lymph nodes, and clinically normal skin or pelvic mucosa was measured. In addition, plasma levels were determined in all of the patients for the platelet-derived chemokine beta-thromboglobulin (beta-TG) and for IFN-gamma, interleukin (IL)-2, IL-4, IL-5, and IL-10, along with serum IgE levels and blood eosinophils. Plasma RANTES levels were found to be higher in order of stages IV, III, II, and I of each cancer except for stage I. A marked increase in plasma RANTES level (> 10,000 pg/ml) was found in 27% of patients with progressive malignancy but in none of those in clinical remission. The platelet RANTES content was correspondingly decreased in those patients with increased plasma RANTES levels. Beta-TG showed a pattern similar to RANTES both in plasma and platelets, but with much less dramatic differences between patients with different stages of disease. Other allergic parameters, IgE, eosinophils and plasma IFN-gamma, IL-2, -5, and -10, were not elevated in the cancer patients. The RANTES content was markedly elevated in the primary tumor and metastatic lesions (lymph node or skin) from all of the patients with breast or cervical cancer, irrespective of the plasma RANTES level. In addition, in patients with progressive breast or cervical cancer, but not in patients thought to be cured of these tumors, the RANTES content was markedly increased in clinically normal tissue taken from near the operative site several months postoperatively, as well as in intact skin or mucosa taken perioperatively near the excised tumor. This study suggests an as-yet-undefined but important role played by RANTES in carcinogenesis, as well as the possibility that a RANTES assay in tissue surrounding a tumor or postoperative tumor site may help predict prognosis in these patients.
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PMID:Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer. 1123 81

Non-small cell lung cancer is characterized by a specific metastatic pattern. The mechanism for organ-specific metastasis is poorly understood, although evidence has suggested that the chemokine stromal derived factor-1 (CXCL12) and its cognate receptor CXCR4 may regulate breast cancer metastasis. We hypothesized that the CXCL12-CXCR4 biological axis is important in mediating non-small cell lung cancer metastases. Our results indicate that both non-small cell lung cancer tumor specimens resected from patients and non-small cell lung cancer cell lines express CXCR4, but not CXCL12. Non-small cell lung cancer cell lines undergo chemotaxis in response to CXCL12. CXCL12-CXCR4 activation of non-small cell lung cancer cell lines showed intracellular calcium mobilization and mitogen-activated protein kinase activation with enhanced extracellular signal-related kinase-1/2 phosphorylation without change in either proliferation or apoptosis. Target organs in a murine model that are the preferred destination of human non-small cell lung cancer metastases elaborate higher levels of CXCL12 than does the primary tumor, and suggest the generation of chemotactic gradients. The administration of specific neutralizing anti-CXCL12 antibodies to severe combined immunodeficient mice expressing human non-small cell lung cancer abrogated organ metastases, without affecting primary tumor-derived angiogenesis. These data suggest that the CXCL12-CXCR4 biological axis is involved in regulating the metastasis of non-small cell lung cancer.
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PMID:The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases. 1262 53

The mechanisms by which malignant tumors leave the primary tumor site, invade lymphatics, and metastasize to regional lymph nodes (RLNs) are complex and interrelated. Although the phenomenon of lymph node metastasis has been recognized for over 200 years, the exact mechanisms have only recently been the subject of intense interest and sophisticated experimentation. Sentinel lymph node biopsy has rapidly entered the clinical mainstream for melanoma and breast carcinoma, and this technique has provided confirmation of the orderly anatomic progression of tumor cells from primary site to the RLNs through lymphatic capillaries and trunks. Exciting studies involving the pathophysiology of interstitial fluid pressure in tumors and the peritumoral extracellular matrix have focused on lymphatic flow and tumor microenvironment and microcirculation. Molecular techniques have led to the definition of unique markers found on lymphatic endothelial cells. These markers have enabled scientists to identify peritumoral and intratumoral lymphatics and to visualize the ingrowth of tumor cells into the lumena of lymphatic capillaries. Tumor-secreted cytokines, such as vascular endothelial growth factors (VEGF)-C and -D, bind to VEGF receptors on lymphatic endothelial cells and induce proliferation and growth of new lymphatic capillaries; this process is similar to the well-known mechanism of angiogenesis, which results from the proliferation of new blood vessel capillaries. Lymphangiogenesis is associated with an increased incidence of RLN metastasis, and it is possible that this step is essential to the metastatic process. Directional movement toward lymphatics and lymph nodes appears to follow a chemokine gradient, and it is likely that some tumor cells that express certain types of chemokine receptors are more likely to metastasize to the RLNs. In contrast, tumor cells that do not express specific receptors that are responsive to lymphatic chemokines may not metastasize. New knowledge regarding the molecules involved in these processes should enable improvements in prognostic and possibly therapeutic approaches to the management of malignant tumors.
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PMID:Insights into the mechanisms of lymph node metastasis. 1287 64

Small-cell lung cancer (SCLC) is an aggressive, rapidly metastasizing neoplasm. The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) is constitutively secreted by marrow stromal cells and plays a key role for homing of hematopoietic cells to the marrow. Here, we report that tumor cells from patients with SCLC express high levels of functional CXCR4 receptors for the chemokine CXCL12. Reverse transcriptase-polymerase chain reaction and flow cytometry demonstrated CXCR4 mRNA and CXCR4 surface expression in SCLC cell lines. Immunohistochemistry of primary tumor samples from SCLC patients revealed high expression of CXCR4. CXCL12 elicited CXCR4 receptor endocytosis, actin polymerization, and a robust activation of phospho-p44/42 mitogen-activated protein kinase in SCLC cells. Furthermore, CXCL12 induced SCLC cell invasion into extracellular matrix and firm adhesion to marrow stromal cells. Stromal cell adhesion of SCLC cells was significantly inhibited by the specific CXCR4 antagonist T140, pertussis toxin, antivascular cell adhesion molecule-1(VCAM-1) antibodies, and CS-1 peptide, demonstrating the importance of CXCR4 chemokine receptor activation and alpha4beta1 integrin binding, respectively. In addition, CXCL12 enhanced the adhesion of SCLC cells to immobilized VCAM-1, demonstrating that CXCR4 chemokine receptors can induce integrin activation on SCLC cells. As SCLC has a high propensity for bone marrow involvement, our findings suggest that CXCR4 chemokine receptors and alpha4beta1 integrins play a critical role in the interaction of SCLC cells with stromal cells in the tumor microenvironment.
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PMID:Functional expression of CXCR4 (CD184) on small-cell lung cancer cells mediates migration, integrin activation, and adhesion to stromal cells. 1460 50

The natural course of cutaneous melanoma (CM) is determined by its metastatic spread and depends on tumor thickness, ulceration, gender, localization, and the histologic subtype of the primary tumor. CM metastasis develops via three main metastatic pathways and occurs as satellite or in-transit metastasis, as regional lymph node metastasis or as distant metastasis at the time of primary recurrence. About 50% of all CM patients with tumor progression firstly develop regional lymph node metastases. In the other 50% the first metastases are satellite or in-transit metastases (about 20%), or immediately distant metastases (about 30%). Development of distant metastasis appears to be an early event in metastatic spread and may in the majority of cases originate from the primary tumor, only few cases may develop secondarily to locoregional metastasis. Reporting of organ involvement in distant metastasis greatly differs between the results of imaging techniques and autopsy results in respect to the metastatic patterns detected, pointing out that there is a need of improved imaging systems. Proliferation, neovascularization, lymphangiogenesis, invasion, circulation, and embolism are important steps in the pathogenesis of CM metastasis, with tumor vascularity as an important independent significant prognostic factor. The expression of chemokine receptors in cancer cells associated with the expression of the respective chemokine receptor ligands in the target sites of the metastasis is an interesting observation which may stimulate the development of new therapeutic strategies.
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PMID:The natural course of cutaneous melanoma. 1522 23

Cytokine and chemokine gradients are central to the directed movement of cells in both homeostatic and pathological processes. Most cancers have a complex chemokine network which can influence immune responses to the tumor, direct the extent and cellular composition of the leukocyte infiltrate and also play a role in angiogenesis. Tumor cells can also hijack the chemokine system and gain expression of certain chemokine receptors and respond to specific chemokine gradients. Chemokine receptor expression and activation on malignant cells may be central to the growth, survival and migration of cancer cells from the primary tumor. Chemokine receptors, both CC and CXC have been detected on malignant cells and the relevant ligands are sometimes expressed at the tumor site and at sites of tumor spread, suggesting a role for the chemokine family in malignant growth and metastasis.
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PMID:The chemokine network in cancer--much more than directing cell movement. 1534 23

We investigated in the current study the effect of TX-1877, a bifunctional hypoxic cell radiosensitizer, in augmenting anticancer host response. In the syngeneic squamous cell carcinoma-bearing mouse model, a single administration of TX-1877 significantly inhibited the primary tumor growth as well as lung metastasis. TX-1877 administration resulted in a significant infiltration of immune cells, such as CD4+T, CD8+T cells, macrophages and dendritic cells (DCs), and an increased expression of chemokines for cytotoxic T lymphocytes (CTLs), helper T-cell 1 (Th1) cells, monocytes/macrophages and DCs, in tumor tissues. Nitric oxide (NO) production and the expression of inducible NO synthase (iNOS) and interferon-gamma, a major Th1 cytokine that plays a major role in anticancer immunity, were also enhanced. Furthermore, neutralization of NO by N-monomethyl-L-arginine acetate resulted in a marked inhibition of the antitumor effect of TX-1877. In tumor-draining lymph nodes, MHC class I-restricted CD8+ memory CTLs specific for inoculated cancer cells were induced by TX-1877. In in vitro experiments, TX-1877 induced chemokines and iNOS/NO in several types of culture cells. These findings strongly suggested that TX-1877 induces migration of CD8+CTLs, CD4+Th1 cells, macrophage/monocytes and dendritic cells into the tumor site, and that this migration is mediated by chemokine induction. In addition, it was suggested that NO produced by several types of cells stimulated by TX-1877 in the tumor sites plays a major role in the anticancer effect of TX-1877. TX-1877 was thus shown to be an effective immunopotentiator as well as a hypoxic cell radiosensitizer.
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PMID:TX-1877, a bifunctional hypoxic cell radiosensitizer, enhances anticancer host response: immune cell migration and nitric oxide production. 1582 72

Breast and kidney-expressed chemokine (BRAK) CXCL14 is a new CXC chemokine with unknown function and receptor selectivity. The majority of head and neck squamous cell carcinoma (HNSCC) and some cervical squamous cell carcinoma do not express CXCL14 mRNA, as opposed to constitutive expression by normal oral squamous epithelium. In this study, we demonstrate that the loss of CXCL14 in HNSCC cells and at HNSCC primary tumor sites was correlated with low or no attraction of dendritic cell (DC) in vitro, and decreased infiltration of HNSCC mass by DC at the tumor site in vivo. Next, we found that recombinant human CXCL14 and CXCL14-positive HNSCC cell lines induced DC attraction in vitro, whereas CXCL14-negative HNSCC cells did not chemoattract DC. Transduction of CXCL14-negative HNSCC cell lines with the human CXCL14 gene resulted in stimulation of DC attraction in vitro and increased tumor infiltration by DC in vivo in chimeric animal models. Furthermore, evaluating the biologic effect of CXCL14 on DC, we demonstrated that the addition of recombinant human CXCL14 to DC cultures resulted in up-regulation of the expression of DC maturation markers, as well as enhanced proliferation of allogeneic T cells in MLR. Activation of DC with recombinant human CXCL14 was accompanied by up-regulation of NF-kappaB activity. These data suggest that CXCL14 is a potent chemoattractant and activator of DC and might be involved in DC homing in vivo.
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PMID:Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo. 1584 47

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