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: Tumour-derived PDGFRβ + (platelet-derived growth factor receptor β) progenitor perivascular cells (PPCs) that have the ability to differentiate into pericytes and regulate vessel stability and vascular survival in tumours are identified.
Abstract: The microvasculature consists of endothelial cells and their surrounding pericytes. Few studies on the regulatory mechanisms of tumour angiogenesis have focused on pericytes. Here we report the identification of tumour-derived PDGFRβ+ (platelet-derived growth factor receptor β) progenitor perivascular cells (PPCs) that have the ability to differentiate into pericytes and regulate vessel stability and vascular survival in tumours. A subset of PDGFRβ+ PPCs is recruited from bone marrow to perivascular sites in tumours. Specific inhibition of PDGFRβ signalling eliminates PDGFRβ+ PPCs and mature pericytes around tumour vessels, leading to vascular hyperdilation and endothelial cell apoptosis in pancreatic islet tumours of transgenic Rip1Tag2 mice.
554 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...entiates into pericytes and stabilizes tumor vessels (17)....
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TL;DR: It is concluded that the use of MMP inhibitors to treat cancer should be considered carefully because of the multifunctionality of gelatinases, it is unpredictable at what stage of cancer development and in which processes gelatinase activity is involved.
501 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...expression levels of MMP2 and MMP9 correlate with tumor progression (27)....
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TL;DR: CCR1 has nonredundant functions in hematopoiesis, host defense, and inflammation, and influences the inflammatory response not only through direct effects on leukocyte chemotaxis, but also through effects on the type 1–type 2 cytokine balance.
Abstract: CC chemokine receptor 1 (CCR1) is expressed in neutrophils, monocytes, lymphocytes, and eosinophils, and binds the leukocyte chemoattractant and hematopoiesis regulator macrophage inflammatory protein (MIP)-1α, as well as several related CC chemokines. Four other CCR subtypes are known; their leukocyte and chemokine specificities overlap with, but are not identical to, CCR1, suggesting that CCR1 has both redundant and specific biologic roles. To test this, we have developed CCR1-deficient mice (−/−) by targeted gene disruption. Although the distribution of mature leukocytes was normal, steady state and induced trafficking and proliferation of myeloid progenitor cells were disordered in −/− mice. Moreover, mature neutrophils from −/− mice failed to chemotax in vitro and failed to mobilize into peripheral blood in vivo in response to MIP-1α. Consistent with this, −/− mice had accelerated mortality when challenged with Aspergillus fumigatus , a fungus controlled principally by neutrophils. To test the role of CCR1 in granuloma formation, we injected Schistosoma mansoni eggs intravenously, and observed a 40% reduction in the size of lung granulomas in −/− mice compared to +/+ littermates. This was associated with increased interferon-γ and decreased interleukin-4 production in −/− versus +/+ lung lymph node cells stimulated with egg-specific antigen, suggesting that CCR1 influences the inflammatory response not only through direct effects on leukocyte chemotaxis, but also through effects on the type 1–type 2 cytokine balance. Thus CCR1 has nonredundant functions in hematopoiesis, host defense, and inflammation.
441 citations
TL;DR: Cathepsins are now emerging as major players in tumor progression, making them potential drug targets for a wide range of human cancers.
Abstract: Cysteine cathepsins are a family of lysosomal proteases that are often upregulated in various human cancers, and have been implicated in distinct tumorigenic processes such as angiogenesis, proliferation, apoptosis and invasion. During cancer progression, cathepsins are often translocated to the cell surface of tumor cells or are secreted into the extracellular milieu, where they can promote tumor invasion through several possible mechanisms. First, they can directly cleave components of the extracellular matrix and basement membrane, essentially clearing a path for the migration of tumor cells away from the primary tumor mass. Second, at the cell membrane, cathepsins can direct a proteolytic cascade in which they activate other proteases such as matrix metalloproteinases and urokinase plasminogen activator, which in turn promote invasion. Finally, cleavage of the cell adhesion protein, E-cadherin, at the cell surface can disrupt adherens junctions and thus facilitate cancer cell migration and invasion. Therefore, cathepsins are now emerging as major players in tumor progression, making them potential drug targets for a wide range of human cancers.
400 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: It is shown that a new type of immature myeloid cell (iMC) is recruited from the bone marrow to the tumor invasion front and accumulation of iMCs that promote tumor invasion in cis-Apc/Smad4 mice.
Abstract: Inactivation of TGF-beta family signaling is implicated in colorectal tumor progression. Using cis-Apc(+/Delta716) Smad4(+/-) mutant mice (referred to as cis-Apc/Smad4), a model of invasive colorectal cancer in which TGF-beta family signaling is blocked, we show here that a new type of immature myeloid cell (iMC) is recruited from the bone marrow to the tumor invasion front. These CD34(+) iMCs express the matrix metalloproteinases MMP9 and MMP2 and the CC-chemokine receptor 1 (CCR1) and migrate toward the CCR1 ligand CCL9. In adenocarcinomas, expression of CCL9 is increased in the tumor epithelium. By deleting Ccr1 in the background of the cis-Apc/Smad4 mutant, we further show that lack of CCR1 prevents accumulation of CD34(+) iMCs at the invasion front and suppresses tumor invasion. These results indicate that loss of transforming growth factor-beta family signaling in tumor epithelium causes accumulation of iMCs that promote tumor invasion.
269 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...Hematopoietic cells expressing CD11b and a granulocyte marker Gr-1 also promote tumor growth by increasing angiogenesis and vasculogenesis (16)....
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...Similar to the cis-Apc/Smad4 polyps, the CCR1 cells that expressed MMP9 infiltrated at the invasion front of some human colon cancers with TGFBR2 mutations (13), suggesting the key roles of the stromal cells that express MMPs in invasion....
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...In a recent study, we found that the invading tumor glands of the cis-Apc/Smad4 adenocarcinomas were associated with clusters of ‘‘immature myeloid cells’’ that expressed myeloid progenitor cell marker CD34, pan-leukocyte marker CD45, and myeloid cell marker CD11b (13)....
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...For example, CD11b+ monocytes that express Tie-2 angiopoietin receptor promote angiogenesis and subsequent tumor growth (15)....
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...Smad4 polyps (13), excluding its contribution to the recruitment of the CCR1 immature myeloid cells....
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