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 demonstrated that monocytes expressing the Tie2 receptor (Tie2-expressing monocytes [TEMs]) are a distinct hematopoietic lineage of proangiogenic cells that are selectively recruited to spontaneous and orthotopic tumors and promote angiogenesis in a paracrine manner.
1,266 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...For example, CD11b monocytes that express Tie-2 angiopoietin receptor promote angiogenesis and subsequent tumor growth (15)....
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TL;DR: The matrix metalloproteinases mediate homeostasis of the extracellular environment and have multiple signalling activities that are commonly altered during tumorigenesis and that might serve as intervention points for anticancer drugs.
Abstract: The matrix metalloproteinases (MMPs) mediate homeostasis of the extracellular environment. They have multiple signalling activities that are commonly altered during tumorigenesis and that might serve as intervention points for anticancer drugs. However, there are many criteria to consider in validating MMPs as drug targets and for the development of MMP inhibitors. The inhibition of some MMPs could have pro-tumorigenic effects (making them anti-targets), counterbalancing the benefits of target inhibition. These effects might partially account for the failure of MMP inhibitors in clinical trials. What are the major challenges in MMP target validation and MMP-inhibitor-drug development?
1,134 citations
TL;DR: This work provides the first direct evidence for a synergistic interaction between macrophages and tumor cells during cell migration in vivo and indicates a mechanism for how macrophage may contribute to metastasis.
Abstract: Invasion of tumor cells into the surrounding connective tissue and blood vessels is a key step in the metastatic spread of breast tumors. Although the presence of macrophages in primary tumors is associated with increased metastatic potential, the mechanistic basis for this observation is unknown. Using a chemotaxis-based in vivo invasion assay and multiphoton-based intravital imaging, we show that the interaction between macrophages and tumor cells facilitates the migration of carcinoma cells in the primary tumor. Gradients of either epidermal growth factor (EGF) or colony-stimulating factor 1 (CSF-1) stimulate collection into microneedles of tumor cells and macrophages even though tumor cells express only EGF receptor and macrophages express only CSF-1 receptor. Intravital imaging shows that macrophages and tumor cells migrate toward microneedles containing either EGF or CSF-1. Inhibition of either CSF-1– or EGF-stimulated signaling reduces the migration of both cell types. This work provides the first direct evidence for a synergistic interaction between macrophages and tumor cells during cell migration in vivo and indicates a mechanism for how macrophages may contribute to metastasis.
1,122 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...colony-stimulating factor-1 (CSF-1) and recruit macrophages to the tumor (10, 19), we found no expression of CSF-1 in the cis-Apc/...
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TL;DR: Evidence is provided that Gr+CD11b+ cells of immune origin induced by tumors directly contribute to tumor growth and vascularization by producing MMP9 and differentiating into ECs.
1,084 citations
"Keeping Out the Bad Guys: Gateway t..." refers background in this paper
...CD11b and a granulocyte marker Gr-1 also promote tumor growth by increasing angiogenesis and vasculogenesis (16)....
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TL;DR: The authors showed that mutations in the DPC4 (SMAD4) gene play a significant role in the malignant progression of colorectal tumors in mice. But, their experiments were performed on Apc Δ 716 knockout mice, a model for human familial adenomatous polyposis.
598 citations
Additional excerpts
...As a model of colorectal tumor progression, we earlier constructed compound mutant mouse strain ‘‘cis-Apc/Smad4 ’’ that carries homozygous inactivation of both Apc and Smad4 genes specifically in the tumor epithelium (11)....
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