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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Distinct biologic and histopathological features characterizing each stage of tumor progression toward a more aggressive phenotype have been defined in the human melanocytic cell system. One of the most significant aspects accompanying melanoma progression is the acquisition of growth autonomy and the expression of multiple growth factors and receptors by tumor cells but not by normal melanocytes. Among the growth factors produced by melanoma cells, bFGF, TGF-alpha, TGF-beta, PDGF A and B chains, MGSA, and interleukins have been extensively characterized. The complex signaling networks mediated by these melanoma-derived factors are responsible for the autocrine growth stimulation of melanoma cells and for paracrine actions of growth factors in the generation of a microenvironment favorable for tumor survival and invasion. bFGF is the best characterized candidate for autocrine stimulation in melanoma cells. In addition, bFGF and other growth factors not apparently involved in autocrine loops have been shown to activate neighboring stromal cells and to participate in angiogenesis, fibrous stroma formation, activation of proteolytic enzymes produced by normal cells, promotion of adhesive interactions between tumor cells and extracellular matrix and endothelium, and suppression of local immunity. Experimental models that can account for the complex interactions between normal and tumor cells are needed to further explore the roles of autocrine and paracrine actions of growth factors and their receptors in melanoma development and progression.
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PMID:Autocrine and paracrine roles for growth factors in melanoma. 751 92

The expression of the CXC chemokine MGSA is often deregulated during viral infection, chronic inflammation, and melanoma tumor progression. In Hs294T melanoma cells, the increased constitutive expression of MGSA is due to increased gene transcription. Moreover, nuclear extracts from unstimulated Hs294T cells contain 19-fold more immunoreactive NF-kappaB p65 than that observed in normal retinal pigment epithelial (ARPE) cells. This increase in NF-kappaB p65 correlates with increased NF-kappaB DNA binding activity in Hs294T nuclear extracts. After stimulation with interleukin 1, Western and electrophoretic mobility shift assay analysis indicate that in both cell types, additional activated NF-kappaB p65 is translocated to the nucleus. However, the rate of postinduction repression of NF-kappaB DNA binding is delayed in Hs294T melanoma cells compared to ARPE cells. Western analysis of whole-cell lysates from both Hs294T and ARPE cells indicates that protein levels of the inhibitor of NF-kappaB, I-kappaB alpha, are 3-fold lower in Hs294T cells. The decrease in I-kappaB alpha cannot be attributed to alterations in the transcription or translation of I-kappaB alpha. Rather, the posttranslational processing has been altered. In Hs294T cells, the half-life of the I-kappaB alpha protein is 45 min, compared to 120 min in ARPE cells. These results indicate that in Hs294T melanoma cells the equilibrium between I-kappaB alpha degradation and resynthesis has been altered, leading to constitutive nuclear translocation and activation of NF-kappaB. Similar mechanisms could also operate in other tumorigenic processes, as well as in viral and chronic inflammatory disorders, to produce high constitutive and unregulated chemokine expression.
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PMID:Enhanced degradation of I-kappaB alpha contributes to endogenous activation of NF-kappaB in Hs294T melanoma cells. 923 Feb 19

Chemokines represent a large family of polypeptide signaling molecules that are notable for their role in chemotaxis, leukocyte homing, directional migration, and G protein coupled receptor activation. Chemo kines have recently been implicated in tumor progression and metastasis. The demonstration of chemokine expression and receptor activation in melanoma tumor cells themselves, and the tumor infiltrating leukocytes, may have important implications in terms of tumor progression and tumor cell homing to metastatic sites. In addition to their chemotactic and cell homing properties, chemokines and their receptors also play a part in other biologic functions relevant to oncogenesis, including cell proliferation, protease induction, tumor growth, and angiogenesis. Melanomas, and the cells derived from them, have been found to express a number of chemokines, including CXCL8 (interleukin-8), CXCL1-3 (MGSA-GROalpha-gamma), CCL5 (RANTES), and CCL2 (monocyte chemotactic protein-1), which have been implicated in tumor growth and progression. Furthermore, recent studies have demonstrated organ-specific patterns of melanoma metastasis that correlate with their expression of specific chemokine receptors, including CXCR4, CCR7, and CCR10. This review will focus on the current biology of chemokines and chemokine receptors in the context of understanding their potential roles in melanoma progression and metastasis, and is not meant to be a comprehensive review of chemokine biology. Continued understanding and progress in the determination of the role of chemokines and their receptors in tumorigenesis and metastasis, including melanoma, may lead to novel approaches in the treatment and management of this disease.
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PMID:The role of chemokines in melanoma tumor growth and metastasis. 1206 Mar 84

The endothelin pathway plays a critical role in melanoma tumor progression by a variety of mechanisms that enhance tumor cell growth, invasion, and metastasis. Here, we investigate the effect of this pathway on CXC chemokine expression in human melanoma cells and melanocytes. As determined by ELISA, endothelin-1 (ET-1) induces CXCL1 and CXCL8 secretion in three human melanoma cell lines in a concentration-dependent fashion. These responses are mediated by the endothelin-B receptor and are sustained over a 40 h time course. ET-1 does not induce CXCL1 secretion in primary human melanocytes but ET-3, an endothelin isoform, induces a low level of CXCL1 secretion in certain cultures. Neither ET-1 nor ET-3 induces secretion of CXCL8 in primary human melanocytes; thus, this response may be specific for melanocytic cells that have undergone malignant transformation. We have previously demonstrated that ET-1 induces changes in the expression of adhesion molecules in melanoma cells such that invasion and metastasis are favored. This study demonstrates that ET-1 additionally induces secretion of CXC chemokines critical for melanoma metastasis and tumor progression.
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PMID:Endothelin-1 induces CXCL1 and CXCL8 secretion in human melanoma cells. 1609 41

The current understanding of the interaction between the endothelium and cancer cells is fundamentally based on the concept that endothelial cells are responsive to differentiation and survival signals originating from the tumor cells. Whereas the effect of tumor cell-secreted factors on angiogenesis is well established, little is known about the effect of factors secreted by endothelial cells on tumor cell gene expression and tumor progression. Here, we show that bcl-2 gene expression is significantly higher in the tumor-associated endothelial cells of patients with head and neck squamous cell carcinomas (HNSCC) as compared with endothelial cells from the normal oral mucosa. Bcl-2 induces vascular endothelial growth factor (VEGF) expression in neovascular endothelial cells through a signal transducer and activator of transcription 3 (STAT3)-mediated pathway. Endothelial cell-derived VEGF signals through VEGFR1 and induces expression of Bcl-2 and the proangiogenic chemokines CXCL1 and CXCL8 in HNSCC cells. Notably, inhibition of Bcl-2 expression in neovascular endothelial cells with RNA interference down-regulates expression of Bcl-2, CXCL8, and CXCL1 in HNSCC cells, and is sufficient to inhibit growth and decrease the microvessel density of xenografted HNSCC in immunodeficient mice. Together, these results show that Bcl-2 is the orchestrator of a cross-talk between neovascular endothelial cells and tumor cells, which has a direct effect on tumor growth. This work identifies a new function for Bcl-2 in cancer biology that is beyond its classic role in cell survival.
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PMID:Bcl-2 orchestrates a cross-talk between endothelial and tumor cells that promotes tumor growth. 1794 98

The incidence of cancers that metastasize to the peritoneum increases with age. Intraperitoneal cancer dissemination depends largely on angiogenesis and interactions with the peritoneal mesothelium. We assessed the proangiogenic potential of human peritoneal mesothelial cells. Conditioned media collected from these cells at senescence stimulated proliferation of endothelial cells to a significantly greater extent compared to media from early-passage cells. The effect was accompanied by a significantly increased release of proangiogenic mediators -- VEGF, CXCL1/GROalpha, CXCL8/IL-8, and CCL2/MCP-1. These results indicate that the senescent mesothelium exhibits increased angiogenic activity, which may contribute to accelerated intraperitoneal cancer progression in the aged.
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PMID:Senescence induces a proangiogenic switch in human peritoneal mesothelial cells. 1859 86

The G protein-coupled protease-activated receptors (PAR) are key signaling components for proteases in vascular biology and tumor progression. To address the contributions of PAR1 and PAR2 to breast cancer development, we established cohorts of mouse mammary tumor virus-polyoma middle T (PyMT) PAR1(-/-) and PAR2(-/-) mice, considering that the PyMT model recapitulates aspects of human disease. Appearance of palpable tumors, tumor expansion, and metastasis was indistinguishable between wild-type and PAR1(-/-) mice. PAR1(-/-) breast cancer cells were no longer responsive to thrombin in vitro, excluding compensatory up-regulation of alternative thrombin receptors and indicating that thrombin-PAR1 signaling is dispensable in breast tumor microenvironments. In contrast, palpable tumors and multifocal disease developed slower in PAR2(-/-) mice, and as a consequence of delayed tumor onset, metastasis was reduced. Analysis of early tumors showed persistence of adenomas with delayed appearance of vascularized adenocarcinomas in PAR2(-/-) mice. Furthermore, CXCL1 production by early PAR2(-/-) tumors was reduced. These results are consistent with previous xenograft data that implicated breast cancer PAR2 signaling in the induction of proangiogenic growth factors and chemokines. This study establishes that protease signaling contributes to mammary tumor development and that PAR2, rather than the thrombin receptor PAR1, plays a crucial role in the angiogenic switch.
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PMID:Protease-activated receptor (PAR) 2, but not PAR1, signaling promotes the development of mammary adenocarcinoma in polyoma middle T mice. 1875 38

Mutant p53 gain of function contributes to cancer progression, increased invasion and metastasis potentials, and resistance to anticancer therapy. The ability of mutant p53 to acquire its gain of function is shown to correlate with increased expression of progrowth genes, such as c-MYC, MDR1, and NF-kappaB2. However, most of the published studies to identify mutant p53 target genes were performed in a cell system that artificially overexpresses mutant p53. Thus, it remains unclear whether such mutant p53 targets can be regulated by endogenous physiological levels of mutant p53. Here, we utilized SW480 and MIA-PaCa-2 cells, in which endogenous mutant p53 can be inducibly knocked down, to identify mutant p53 target genes that potentially mediate mutant p53 gain of function. We found that knockdown of mutant p53 inhibits GRO1 expression, whereas ectopic expression of mutant R175H in p53-null HCT116 cells increases GRO1 expression. In addition, we found that endogenous mutant p53 is capable of binding to and activating the GRO1 promoter. Interestingly, ectopic expression of GRO1 can rescue the proliferative defect in SW480 and MIA-PaCa-2 cells induced by knockdown of mutant p53. Conversely, knockdown of endogenous GRO1 inhibits cell proliferation and thus abrogates mutant p53 gain of function in SW480 cells. Taken together, our findings define a novel mechanism by which mutant p53 acquires its gain of function via transactivating the GRO1 gene in cancer cells. Thus, targeting GRO1 for cancer therapy would be applicable to a large portion of human tumors with mutant p53, but the exploration of GRO1 as a potential target should take the mutation status of p53 into consideration.
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PMID:Identification of GRO1 as a critical determinant for mutant p53 gain of function. 1925 12

Chemokines are soluble factors shown to play important roles in regulating immune cell recruitment during inflammatory responses and defense against foreign pathogens. De-regulated expression and activity of several chemokine signaling pathways have been implicated in cancer progression, including: CCL2, CCL5, CXCL1 and CXCL12. While studies in the past have focused the role of these chemokine signaling pathways in regulating immune responses, emerging studies show that these molecules regulate diverse cellular processes including angiogenesis, and regulation of epithelial cell growth and survival. New evidence indicates that chemokines are critical for cancer progression and indicate complex and diverse functions in the tumor microenvironment. This review will focus on the contributions of chemokine signaling in regulating cancer microvironment and discuss the utility of targeting or delivering chemokines in cancer therapeutics.
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PMID:Chemokine signaling in cancer: Implications on the tumor microenvironment and therapeutic targeting. 2065 40

Gastric cancer (GC) is a heterogeneous disease that is not well detected by current tumor markers. Identifying molecular markers that can predict the potential for tumor progression is important for appropriate individualized therapy. Using the Cancer Metastasis Research Center microarray database (17K cDNA microarray), we identified genes that were differentially expressed between 96 cancer and 98 normal gastric tissues using significant analysis of microarrays. From these, we selected genes that were overexpressed more than twofold in tumor tissues that encode secreted proteins. The selected genes were validated with ELISA using the sera of 96 GC patients and 48 healthy donors. Our first round of selection included 6510 genes that were differentially expressed between 96 cancer and 98 normal gastric tissues with a minimal false discovery rate of 0.005%. Out of those genes, we picked 386 that encoded secreted proteins based on the SOURCE database. Of these genes, we focused on 55 that were overexpressed more than twofold in GC compared to normal tissues. With Ingenuity Pathway Analysis, we found 34 genes related to cancer. One in particular, chemokine growth-regulated oncogene 1, CXCL1, has been linked to cancer progression in various cancer types, but not yet to GC. Levels of CXCL1 in serum samples of GC patients were significantly higher compared with healthy donors (P < 0.05). Within GC patients, CXCL1 serum levels increased according to tumor stage and lymph node metastasis. The CXCL1 gene appears to be a candidate marker for GC progression.
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PMID:Chemokine growth-regulated oncogene 1 as a putative biomarker for gastric cancer progression. 2073 65


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