Keeping Out the Bad Guys: Gateway to Cellular Target Therapy
01 Nov 2007-Cancer Research (American Association for Cancer Research)-Vol. 67, Iss: 21, pp 10099-10102
TL;DR: It is shown that lack of CCR1 prevents the accumulation of M MP-expressing cells at the invasion front and suppresses tumor invasion, providing the possibility of a novel therapeutic strategy for advanced cancer--prevention of the recruitment of MMP- expressing cells by chemokine receptor antagonist.
Abstract: Tumor-stromal interaction is implicated in many stages of tumor development, although it remains unclear how genetic lesions in tumor cells affect stromal cells. We have recently shown that inactivation of transforming growth factor-beta family signaling within colon cancer epithelium increases chemokine CC chemokine ligand 9 (CCL9) and promotes recruitment of the matrix metalloproteinase (MMP)-expressing stromal cells that carry CC chemokine receptor 1 (CCR1), the cognate receptor for CCL9. We have further shown that lack of CCR1 prevents the accumulation of MMP-expressing cells at the invasion front and suppresses tumor invasion. These results provide the possibility of a novel therapeutic strategy for advanced cancer--prevention of the recruitment of MMP-expressing cells by chemokine receptor antagonist.
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TL;DR: The role of a few proteases and their inhibitors in tumors as a basis for cancer prognostication and therapy is focused on.
Abstract: Proteases are important molecules that are involved in many key physiological processes. Protease signaling pathways are strictly controlled, and disorders in protease activity can result in pathological changes such as cardiovascular and inflammatory diseases, cancer and neurological disorders. Many proteases have been associated with increasing tumor metastasis in various human cancers, suggesting important functional roles in the metastatic process because of their ability to degrade the extracellular matrix barrier. Proteases are also capable of cleaving non-extracellular matrix molecules. Inhibitors of proteases to some extent can reduce invasion and metastasis of cancer cells, and slow down cancer progression. In this review, we focus on the role of a few proteases and their inhibitors in tumors as a basis for cancer prognostication and therapy.
12 citations
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...Therefore, it is not surprising that systemic and prolonged inhibition of MMP activities causes aberrant immune responses and other stromal reactions (Kitamura and Taketo, 2007)....
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TL;DR: Investigation of the development of inflammation and tumors in a murine model of inflammation-induced colorectal cancer using a combined treatment of azoxymethane and dextran sulfate sodium revealed increased colonic inflammation at the molecular level accompanied by enhanced macroscopic tumor development in Cygb-deficient mice.
Abstract: Cytoglobin (Cygb) is a member of the hemoglobin family and is thought to protect against cellular hypoxia and oxidative stress. These functions may be particularly important in inflammation-induced cancer, e.g., in patients with ulcerative colitis (UC). In this study, we investigated the development of inflammation and tumors in a murine model of inflammation-induced colorectal cancer using a combined treatment of azoxymethane and dextran sulfate sodium. A bioinformatics analysis of genome-wide expression data revealed increased colonic inflammation at the molecular level accompanied by enhanced macroscopic tumor development in Cygb-deficient mice. Moreover, the expression of the UC-associated gene neurexophilin and PC-esterase domain family member 4 (Nxpe4) depended on the presence of Cygb in the inflamed colonic mucosa. Compared to wild type mice, RT-qPCR confirmed a 14-fold (p = 0.0003) decrease in Nxpe4 expression in the inflamed colonic mucosa from Cygb-deficient mice. An analysis of Cygb protein expression suggested that Cygb is expressed in fibroblast-like cells surrounding the colonic crypts. Histological examinations of early induced lesions suggested that the effect of Cygb is primarily at the level of tumor promotion. In conclusion, in this model, Cygb primarily seemed to inhibit the development of established microadenomas.
12 citations
TL;DR: The results of this meta-analysis suggest that high LDH5 expression is associated with HIF-1α and poor overall survival in cancer patients.
Abstract: Lactate dehydrogenase 5 (LDH5) is believed to be particularly important and a reliable marker of malignancy. However, it is still controversial whether LDH5 expression can be regarded as a prognostic factor for cancer patients. We reviewed the literature by performing an electronic database search via PubMed to identify eligible studies that assessed the impact of LDH5 as a cancer prognostic marker and its association with HIF-1α. Heterogeneity and publication bias were also assessed. A total of 12 literatures which included 1,892 cancer patients were combined in the final analysis. Meta-analysis revealed that LDH5 overexpression was associated with an unfavorable overall survival (12 studies, 1,597 patients; HR 1.59, 95 % CI 1.17-2.16) and disease/recurrence/progression-free survival (7 studies; 1,086 patients; HR 1.46, 95 % CI 1.04-2.04) among solid tumor patients. Meta-analysis revealed an association between the expression of LDH5 and hypoxia-inducible factors 1 (OR 2.72, 95 % CI 1.66-4.45). Publication bias could not be excluded when investigating the association of LDH5 expression and overall survival. However, when we accounted for publication bias using the trim and fill method, the results remained significant (HR 1.435, 95 % CI 1.071-1.923, P < 0.05) suggesting the stability of our results. Therefore, our study suggested that LDH5 overexpression had a poor prognosis value in cancer patients. The results of this meta-analysis suggest that high LDH5 expression is associated with HIF-1α and poor overall survival in cancer patients.
11 citations
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...Seeking novel molecular targets and developing corresponding inhibitors have always been an interesting topic in cancer research [1]....
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TL;DR: NHL's express functional chemokine receptors, which, at least in part, dictate tissue localisation and perhaps metastatic potential, which are investigated to investigate the role of theChemokine system in the pathology of NHL and as a potential drug target in this disease.
Abstract: Background: Chemokines and their receptors are a large family of molecules that control the trafficking of immune cells during their development and in response to inflammation. Non Hodgkin's lymphoma (NHL) derives from the neoplastic transformation of lymphocytes at different stages of differentiation and may show systemic, nodal and extranodal localisation as well as metastasis in different sites. Objective: To investigate the role of the chemokine system in the pathology of NHL and as a potential drug target in this disease. Method: The expression of chemokines and receptors by different NHL subtypes as well as their likely functional role in terms of lymphoma tissue localisation, lymphoma growth, tumour angiogenesis and recruitment of immune cells are reviewed. The data regarding antagonists or chemokines as potential therapeutic agents for NHL is discussed. Results/conclusions: NHL's express functional chemokine receptors, which, at least in part, dictate tissue localisation and perhaps metastatic po...
11 citations
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...These targets include the CXCR2–CCL2 axis, due to the known activity of CCL2 in promoting infiltration of tumour-promoting macrophages and in favouring angiogenesis, and the CCR7 and CCR1 molecules, thought to play an important role in promoting metastasis of solid tumours [2,54] ....
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...Thus, chemokines produced at the tumour site either by the tumour cells themselves, or by stroma or immune cells infiltrating the tumour, can have tumour-promoting or -inhibiting effects [54] ....
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TL;DR: Using the mHART 1.0 database, it was determined that a failure to mount sufficient macrophage-mediated inflammation was indicative of exacerbated LV dilation.
9 citations
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TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
28,811 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...associated fibroblasts (CAF) stimulate prostate tumor formation (6), not to mention the essential roles of angiogenesis in tumor growth (7, 8)....
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TL;DR: It is shown that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer.
Abstract: Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. This provided the rationale for clinical trials of MMP inhibitors, unfortunately with disappointing results. We now know, however, that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer. With this knowledge in hand, can we rethink the use of MMP inhibitors in the clinic?
5,860 citations
TL;DR: Fibroblasts are a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.
Abstract: Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.
4,232 citations
TL;DR: Using a coimplantation tumor xenograft model, it is demonstrated that carcinoma-associated fibroblasts extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammaries derived from the same patients.
3,373 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...In a breast cancer xenograft model, CXCL12 promotes angiogenesis by recruiting endothelial progenitor cells and stimulates tumor growth (9)....
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...CAFs also promote the growth of breast cancer xenografts (9)....
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TL;DR: Cancer cells possess a broad spectrum of migration and invasion mechanisms and learning more about the cellular and molecular basis of these different migration/invasion programmes will help to understand how cancer cells disseminate and lead to new treatment strategies.
Abstract: Cancer cells possess a broad spectrum of migration and invasion mechanisms. These include both individual and collective cell-migration strategies. Cancer therapeutics that are designed to target adhesion receptors or proteases have not proven to be effective in slowing tumour progression in clinical trials — this might be due to the fact that cancer cells can modify their migration mechanisms in response to different conditions. Learning more about the cellular and molecular basis of these different migration/invasion programmes will help us to understand how cancer cells disseminate and lead to new treatment strategies.
3,064 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...the circulation of patients with adenocarcinomas (12)....
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...Like most epithelial cancers, the cis-Apc/Smad4 adenocarcinomas invade the intestinal wall as protruding glands or sheets, a typical pattern of ‘‘collective migration’’ (12)....
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