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: What models have been developed most recently and what they have taught us about colon cancer formation, progression, and possible treatment strategies are discussed.
Abstract: Genetically engineered mice are essential tools in both mechanistic studies and drug development in colon cancer research. Mice with mutations in the Apc gene, as well as in genes that modify or interact with Apc, are important models of familial adenomatous polyposis. Mice with mutations in the β-catenin signaling pathway have also revealed important information about colon cancer pathogenesis, along with models for hereditary nonpolyposis colon cancer and inflammatory bowel diseases associated with colon cancer. Finally, transplantation models (xenografts) have been useful in the study of metastasis and for testing potential therapeutics. This review discusses what models have been developed most recently and what they have taught us about colon cancer formation, progression, and possible treatment strategies.
233 citations
TL;DR: It is shown that Aes (or Grg5) gene functions as an endogenous metastasis suppressor and inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis.
Abstract: SUMMARY Metastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in Apc D716 intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis.
198 citations
Cites background from "Keeping Out the Bad Guys: Gateway t..."
...The latter tumors were surrounded by immature myeloid cells (iMCs; CD34+CD45+CCR1+) and showed local invasion without intravasation (Kitamura et al., 2007; Kitamura and Taketo, 2007)....
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TL;DR: The results suggested that LDH-A inhibition might offer a promising therapeutic strategy for breast cancer.
Abstract: LDH-A, as the critical enzyme accounting for the transformation from pyruvate into lactate, has been demonstrated to be highly expressed in various cancer cells and its silencing has also been approved relating to increased apoptosis in lymphoma cells. In this study, we intend to investigate the correlation between LDH-A and other clinicopathological factors of breast cancer and whether LDH-A silencing could suppress breast cancer growth, and if so the potential mechanisms. 46 breast cancer specimens were collected to study the relation between LDH-A expression and clinicopathological characteristics including menopause, tumor size, node involvement, differentiation, and pathological subtypes classified by ER, PR, and Her-2. shRNAs were designed and applied to silence LDH-A expression in breast cancer cell lines MCF-7 and MDA-MB-231. The effects of LDH-A reduction on cancer cells were studied by a series of in vitro and in vivo experiments, including cell growth assay, apoptosis evaluation, oxidative stress detection, transmission electron microscopy observation, and tumor formation assay on nude mice. LDH-A expression was found to correlate significantly with tumor size and to be independent for other clinicopathological factors. LDH-A reduction resulted in an inhibited cancer cell proliferation, elevated intracellular oxidative stress, and induction of mitochondrial pathway apoptosis. Meanwhile, the tumorigenic ability of LDH-A deficient cancer cells was significantly limited in both breast cancer xenografts. The Ki67 positive cancer cells were significantly reduced in LDH-A deficiency tumor samples, while the apoptosis ratio was enhanced. Our results suggested that LDH-A inhibition might offer a promising therapeutic strategy for breast cancer.
147 citations
Cites background from "Keeping Out the Bad Guys: Gateway t..."
...Seeking novel molecular targets and developing corresponding inhibitors have always been an interesting topic in cancer research [1, 2]....
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TL;DR: It is suggested that CCR1 antagonists can provide antimetastatic therapies for patients with disseminated colon cancer in the liver because of their role in tumor invasion and metastasis.
Abstract: Recent reports have suggested critical roles of myeloid cells in tumor invasion and metastasis, although these findings have not led to therapeutics. Using a mouse model for liver dissemination, we show that mouse and human colon cancer cells secrete CC-chemokine ligands CCL9 and CCL15, respectively, and recruit CD34+ Gr-1− immature myeloid cells (iMCs). They express CCL9/15 receptor CCR1 and produce matrix metalloproteinases MMP2 and MMP9. Lack of the Ccr1, Mmp2, or Mmp9 gene in the host dramatically suppresses outgrowths of disseminated tumors in the liver. Importantly, CCR1 antagonist BL5923 blocks the iMC accumulation and metastatic colonization and significantly prolongs the survival of tumor-bearing mice. These results suggest that CCR1 antagonists can provide antimetastatic therapies for patients with disseminated colon cancer in the liver.
145 citations
Cites background from "Keeping Out the Bad Guys: Gateway t..."
...These results provide the rationale for application of CCR1 antagonists to colon cancer treatment that targets the MMP-expressing myeloid cells, rather than direct and systemic inhibition ofMMPs (32)....
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TL;DR: The current understanding of the use of genetically engineered mesenchymal stem cells in human disease therapy with emphasis on genetic modifications aimed to improve survival, homing, angiogenesis, and heart function after myocardial infarction is presented.
Abstract: The use of stem cells for tissue regeneration and repair is advancing both at the bench and bedside. Stem cells isolated from bone marrow are currently being tested for their therapeutic potential in a variety of clinical conditions including cardiovascular injury, kidney failure, cancer, and neurological and bone disorders. Despite the advantages, stem cell therapy is still limited by low survival, engraftment, and homing to damage area as well as inefficiencies in differentiating into fully functional tissues. Genetic engineering of mesenchymal stem cells is being explored as a means to circumvent some of these problems. This review presents the current understanding of the use of genetically engineered mesenchymal stem cells in human disease therapy with emphasis on genetic modifications aimed to improve survival, homing, angiogenesis, and heart function after myocardial infarction. Advancements in other disease areas are also discussed.
139 citations
Cites background from "Keeping Out the Bad Guys: Gateway t..."
...C-C chemokine receptor type 1 (CCR1) is a G proteincoupled receptor involved in the recruitment of immune cells to site of inflammation (Kitamura and Taketo, 2007; Zernecke et al., 2008)....
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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.
Abstract: We wish to thank Terry Schoop of Biomed Arts Associates, San Francisco, for preparation of the figures, Cori Bargmann and Zena Werb for insightful comments on the manuscript, and Normita Santore for editorial assistance. In addition, we are indebted to Joe Harford and Richard Klausner, who allowed us to adapt and expand their depiction of the cell signaling network, and we appreciate suggestions on signaling pathways from Randy Watnick, Brian Elenbas, Bill Lundberg, Dave Morgan, and Henry Bourne. R. A. W. is a Ludwig Foundation and American Cancer Society Professor of Biology. His work has been supported by the Department of the Army and the National Institutes of Health. D. H. acknowledges the support and encouragement of the National Cancer Institute. Editorial policy has rendered the citations illustrative but not comprehensive.
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.
Abstract: Fibroblasts often constitute the majority of the stromal cells within a breast carcinoma, yet the functional contributions of these cells to tumorigenesis are poorly understood. Using a coimplantation tumor xenograft model, we demonstrate that carcinoma-associated fibroblasts (CAFs) extracted from human breast carcinomas promote the growth of admixed breast carcinoma cells significantly more than do normal mammary fibroblasts derived from the same patients. The CAFs, which exhibit the traits of myofibroblasts, play a central role in promoting the growth of tumor cells through their ability to secrete stromal cell-derived factor 1 (SDF-1); CAFs promote angiogenesis by recruiting endothelial progenitor cells (EPCs) into carcinomas, an effect mediated in part by SDF-1. CAF-secreted SDF-1 also stimulates tumor growth directly, acting through the cognate receptor, CXCR4, which is expressed by carcinoma cells. Our findings indicate that fibroblasts within invasive breast carcinomas contribute to tumor promotion in large part through the secretion of SDF-1.
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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