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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01 Jan 2009
TL;DR: DILI is challenging to investigate because of its rarity, the lack of experimental models, the number of medications that might cause it, and challenges to diagnosis.
Abstract: Idiosyncratic drug-induced liver injury (DILI) is a rare disorder that is not related directly to dosage and little is known about individuals who are at increased risk. There are no suitable preclinical models for the study of idiosyncratic DILI and its pathogenesis is poorly understood. It is likely to arise from complex interactions among genetic, nongenetic host susceptibility, and environmental factors. Nongenetic risk factors include age, sex, and other diseases (eg, chronic liver disease or human immunodeficiency virus infection). Compound-specific risk factors include daily dose, metabolism characteristics, and propensity for drug interactions. Alcohol consumption has been proposed as a risk factor for DILI from medications, but there is insufficient evidence to support this. Many studies have explored genetic defects that might be involved in pathogenesis and focused on genes involved in drug metabolism and the immune response. Multicenter databases of patients with DILI (the United States Drug Induced Liver Injury Network, DILIGEN, and the Spanish DILI registry) are important tools for clinical and genetic research. A genome-wide association study of flucloxacillin hepatotoxicity has yielded groundbreaking results and many similar studies are underway. Nonetheless, DILI is challenging to investigate because of its rarity, the lack of experimental models, the number of medications that might cause it, and challenges to diagnosis.
43 citations
Dissertation•
01 Jan 2008
39 citations
TL;DR: This review focuses on mutual interactions between ECM proteases and cytokines during cancer development and pregnancy and aims to contribute to the innovative therapeutic intervention in both cancer and pregnancy-related processes.
Abstract: The extracellular matrix proteases act in diverse physiological and pathological processes involving tumor growth, angiogenesis, and pregnancy through the cleavage of extracellular matrix (ECM) and non-matrix proteinaceous substrates. Matrix metalloproteinases (MMPs) constitute a main family among the ECM proteases. Endogenous tissue inhibitors of metalloproteinases (TIMPs), as one kind of MMPs inhibitors (MMPIs), reduce the excessive proteolytic ECM degradation by MMPs. The balance between MMPs and TIMPs plays a major role in cancer tumorigenesis, angiogenesis, as well as embryo implantation and trophoblastic invasion during pregnancy. A variety of literature concerns the correlated changes in MMPs and MMPIs during the formation of cancer and pregnancy-related complications. Importantly, MMPs and TIMPs may act as regulators of signaling pathways through the cleavage of non-matrix substrates, including cytokines, chemokines, and growth factors. In this review, we concentrate on mutual interactions between ECM proteases and cytokines during cancer development and pregnancy. The current knowledge in the field of identified ECM proteases will be contributive to the innovative therapeutic intervention in both cancer and pregnancy-related processes.
37 citations
TL;DR: It is demonstrated here that lack of MMP7 reduces the number and size of tumors in the cis-Apc/Smad4 mice, indicating that M MP7 is required for tumor formation, but not for the invasion or fibrosis of the colon cancer whose SMAD4-dependent TGF-β family signaling is blocked.
35 citations
Cites result from "Keeping Out the Bad Guys: Gateway t..."
...Furthermore, the present results support our novel therapeutic strategy against tumor invasion, which targets MMP-producing stromal iMCs with CCR1 inhibitors, rather than direct inhibition of MMPs produced by the tumor epithelial cells.(32)...
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TL;DR: Recent preclinical and clinical data supporting the view that chemokine pathways are potential therapeutic targets for liver metastasis of colorectal cancer are discussed.
Abstract: Colorectal cancer is the second most common cancer, and is the third leading cause of cancer-related death in Japan. The majority of these deaths is attributable to liver metastasis. Recent studies have provided increasing evidence that the chemokine–chemokine receptor system is a potential mechanism of tumor metastasis via multiple complementary actions: (a) by promoting cancer cell migration, invasion, survival and angiogenesis; and (b) by recruiting distal stromal cells (i.e., myeloid bone marrow-derived cells) to indirectly facilitate tumor invasion and metastasis. Here, we discuss recent preclinical and clinical data supporting the view that chemokine pathways are potential therapeutic targets for liver metastasis of colorectal cancer.
32 citations
References
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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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