Loss of SMAD4 From Colorectal Cancer Cells Promotes CCL15 Expression to Recruit CCR1+ Myeloid Cells and Facilitate Liver Metastasis

Itatani, Yoshiro; Kawada, Kenji; Fujishita, Teruaki; Kakizaki, Fumihiko; Hirai, Hideyo; Matsumoto, Takuya; Iwamoto, Masayoshi; Inamoto, Susumu; Hatano, Etsuro; Hasegawa, Suguru; Maekawa, Taira; Üemoto, Shinji; Sakai, Yoshiharu; Taketo, Makoto Mark

doi:10.1053/j.gastro.2013.07.033

Cited by 109 publications

(126 citation statements)

References 39 publications

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“…Using a mouse model of colorectal cancer liver metastasis, we also demonstrated that CCL9-expressing colorectal cancer cell lines recruit CCR1 þ myeloid cells to expand metastatic foci in the liver (7), and that four distinct types of myeloid cells are recruited to the metastatic foci; CCR1 þ neutrophils, eosinophils monocytes, and fibrocytes (8). In addition to these mouse models, we recently reported that SMAD4 binds directly to the promoter region of human CCL15 (a human ortholog of mouse CCL9) and negatively regulates its expression in vitro (9). In addition, with human specimens of liver metastasis of colorectal cancer, we also showed that loss of SMAD4 in colorectal cancer cells promotes CCL15 expression, recruits CCR1 þ myeloid cells, and facilitates liver metastasis (9).…”

Section: Introductionmentioning

confidence: 70%

“…The presence of CCL15 protein was interpreted as positive when >10% of the tumor cells at the invasion front were stained. We quantified the densities of CCR1 þ cells and CCR3 þ cells at the invasion front of primary colorectal cancer [5-9 fields (0.1mm 2 ) analyzed per one sample], as previously described (9). We adopted immunohistochemistry (IHC) analysis of MLH1 and MSH2, and then interpreted as mismatch repair intact (MMR-I) when both proteins were positive, while as MMR deficient (MMR-D) when either protein was negative (14).…”

Section: Immunohistochemistry Analysismentioning

confidence: 99%

“…In addition to these mouse models, we recently reported that SMAD4 binds directly to the promoter region of human CCL15 (a human ortholog of mouse CCL9) and negatively regulates its expression in vitro (9). In addition, with human specimens of liver metastasis of colorectal cancer, we also showed that loss of SMAD4 in colorectal cancer cells promotes CCL15 expression, recruits CCR1 þ myeloid cells, and facilitates liver metastasis (9). However, it has not been investigated whether the CCL15-CCR1 chemokine axis is correlated with progression of primary colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

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Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through the CCL15–CCR1 Chemokine Axis

Inamoto

Itatani

Yamamoto

et al. 2016

Clinical Cancer Research

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109

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Purpose: We previously reported that loss of SMAD4 promotes chemokine CCL15 expression to recruit CCR1 þ myeloid cells via the CCL15-CCR1 axis, which facilitates metastasis of colorectal cancer to the liver. The purposes of this study were to investigate whether essentially the same mechanism works in tumor invasion of the primary colorectal cancer and to evaluate the clinical importance of CCL15 expression and CCR1 þ cell accumulation.Experimental Design: Using human colorectal cancer cell lines with reduced expression of SMAD4 or CCL15, we investigated tumor growth activities in vivo. We used immunohistochemistry (IHC) to investigate expression of SMAD4, CCL15, and CCR1 with 333 clinical specimens of primary colorectal cancer. We next characterized the CCR1 þ cells using double immunofluorescence staining with several specific cell-type markers. Finally, we determined the serum CCL15 levels in 132 colorectal cancer patients. Results:In an orthotopic xenograft model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1

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Section: Introductionmentioning

confidence: 70%

Section: Immunohistochemistry Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through the CCL15–CCR1 Chemokine Axis

Inamoto

Itatani

Yamamoto

et al. 2016

Clinical Cancer Research

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109

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“…HT29, but not Caco2, is a SMAD4-deficient colon cancer cell and loss of SMAD4 correlates with elevated CCL15 expression. 39,40 This is of particular interest, because in a mouse xenograft model, CCL15 secreted from SMAD4-deficient colon cancer cells recruited CCR1 + cells, resulting in aggressive tumor growth and metastasis. In the same study, it was found that CCL15 positively correlated with a worse survival in patients with CRC.…”

Section: Discussionmentioning

confidence: 99%

“…In the same study, it was found that CCL15 positively correlated with a worse survival in patients with CRC. 39,40 Human MC express surface receptors for CCL15, which are CCR1 and CCR3. 19 Therefore, based on our current data it is reasonable to speculate that MC may be among those infiltrating CCR1 + cells and subsequently contribute to colon cancer growth.…”

Section: Discussionmentioning

confidence: 99%

Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models

Blokhuis

Derks

et al. 2018

OncoImmunology

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Chronic inflammation drives the development of colorectal cancer (CRC), where tumor-infiltrating immune cells interact with cancer cells in a dynamic crosstalk. Mast cells (MC), one of earliest recruited immune cells, accumulate in CRC tissues and their density is correlated with cancer progression. However, the exact contribution of MC in CRC and their interaction with colon cancer cells is poorly understood. Here, we investigated the impact of primary human MC and their mediators on colon cancer growth using 2D and 3D coculture models. Primary human MC were generated from peripheral CD34+ stem cells. Transwell chambers were used to analyze MC chemotaxis to colon cancer. Colon cancer cells HT29 and Caco2 differentially recruited MC by releasing CCL15 or SCF, respectively. Using BrdU proliferation assays, we demonstrated that MC can directly support colon cancer proliferation and this effect was mediated by their cellular crosstalk. 3D coculture models with cancer spheroids further confirmed the pro-tumor effect of MC on colon cancer growth, where direct cell-cell contact is dispensable and increased production of multiple soluble mediators was detected. Moreover, TLR2 stimulation of MC promoted stronger growth of colon cancer spheroids. By examining the transcriptome profile of colon cancer-cocultured MC versus control MC, we identified several MC marker genes, which were deregulated in expression. Our study provides an advanced in vitro model to investigate the role of human MC in cancer. Our data support the detrimental role of MC in CRC development and provide a molecular insight into the cellular crosstalk between MC and colon cancer cells.

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Determinants of metastatic competency in colorectal cancer

et al. 2017

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Colorectal cancer (CRC) is one of the most common cancer types and represents a major therapeutic challenge. Although initial events in colorectal carcinogenesis are relatively well characterized and treatment for early‐stage disease has significantly improved over the last decades, the mechanisms underlying metastasis – the main cause of death – remain poorly understood. Correspondingly, no effective therapy is currently available for advanced or metastatic disease. There is increasing evidence that colorectal cancer is hierarchically organized and sustained by cancer stem cells, in concert with various stromal cell types. Here, we review the interplay between cancer stem cells and their microenvironment in promoting metastasis and discuss recent insights relating to both patient prognosis and novel targeted treatment strategies. A better understanding of these topics may aid the prevention or reduction of metastatic burden.

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Loss of SMAD4 From Colorectal Cancer Cells Promotes CCL15 Expression to Recruit CCR1+ Myeloid Cells and Facilitate Liver Metastasis

Cited by 109 publications

References 39 publications

Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through the CCL15–CCR1 Chemokine Axis

Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through the CCL15–CCR1 Chemokine Axis

Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models

Determinants of metastatic competency in colorectal cancer

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