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.
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.
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: It is shown that uPARAP/Endo180 has a key role in the degradation of collagen during mammary carcinoma progression, as evidenced by the abrogation of cellular collagen uptake, tumor fibrosis, and blunted tumor growth.
Abstract: We recently reported that uPARAP/Endo180 can mediate the cellular uptake and lysosomal degradation of collagen by cultured fibroblasts. Here, we show that uPARAP/Endo180 has a key role in the degradation of collagen during mammary carcinoma progression. In the normal murine mammary gland, uPARAP/Endo180 is widely expressed in periductal fibroblast-like mesenchymal cells that line mammary epithelial cells. This pattern of uPARAP/Endo180 expression is preserved during polyomavirus middle T–induced mammary carcinogenesis, with strong uPARAP/Endo180 expression by mesenchymal cells embedded within the collagenous stroma surrounding nests of uPARAP/Endo180-negative tumor cells. Genetic ablation of uPARAP/Endo180 impaired collagen turnover that is critical to tumor expansion, as evidenced by the abrogation of cellular collagen uptake, tumor fibrosis, and blunted tumor growth. These studies identify uPARAP/Endo180 as a key mediator of collagen turnover in a pathophysiological context.
130 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...The ineffectiveness of MMP inhibitors may be explained partly by the recent findings that cancer stromal cells have nonMMP proteinases that degrade ECM, such as cathepsins (31) and uPARAP/Endo 180 (32)....
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TL;DR: The mechanism of action of the CCR1 antagonist is examined in in vitro flow assays over microvascular endothelium and it is discovered that the antagonist blocks the firm adhesion of monocytes triggered by RANTES on inflamed endothelia, demonstrating a significant role for CCR 1 in allograft rejection.
125 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...Namely, BX471 reduces a clinical score in a rat experimental allergic encephalomyelitis model of multiple sclerosis (25) and blocks rat heart transplant rejection in combination with cyclosporine (26)....
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Dissertation•
01 Jan 2008
39 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...Furthermore, we have shown that CXCR3 expressed on melanoma and colon cancer cells promotes their metastasis to the lymph nodes but not to the lung (21, 22)....
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TL;DR: The identification, chemistry, biology and therapeutic potential of BX 471 a potent CCR1 antagonist that is currently in the clinic for a variety of indications are discussed.
Abstract: Chemokines belong to a large family of chemoattractant molecules involved in the directed migration of immune cells. They achieve their cellular effects by direct interaction with cell surface receptors. The chemokine receptor CCR1 appears to be involved in a variety of proinflammatory and autoimmune diseases and this makes it a very attractive therapeutic target. This review discusses the identification, chemistry, biology and therapeutic potential of BX 471 a potent CCR1 antagonist that is currently in the clinic for a variety of indications.
37 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...with various autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and organ transplant rejection (24)....
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...Therefore, some pharmaceutical companies have developed CCR1 antagonists and are testing some compounds in phase II clinical trials for multiple sclerosis and rheumatoid arthritis (24)....
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