Effects of Intratumoral Injection of CCL2 on Monocyte–Endothelial Cell Interactions in Mouse Pancreatic Cancer

Okudaira, Keisuke; Tsuzuki, Yoshikazu; Hokari, Ryota; Miyazaki, Junichi; Mataki, Norikazu; Komoto, Shunsuke; Okada, Yoshikiyo; Kawaguchi, Atsushı; Nagao, Shigeaki; Itoh, Kazuro; Miura, Soichiro

doi:10.1080/10739680601139393

Cited by 8 publications

(9 citation statements)

References 34 publications

(35 reference statements)

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“… (a) Representative photomicrographs of the effects of CCL1 (10 ng/mL), CCL2 (10 ng/mL), CCL12 (10 ng/mL) and CCL21 (10 ng/mL) after 18‐h stimulation on the immunohistochemical expression of E‐selectin, ( 1,5,9,13 ) P‐selectin, ( 2,6,10,14 ) VCAM‐1, ( 3,7,11,15 ) and ICAM‐1 ( 4,8,12,16 ) on cultured human LECs. (b) Representative photomicrographs of the effects of TNF‐α (10 ng/mL) and LPS (100 ng/mL) after 18‐h stimulation on the immunohistochemical expression of adhesion molecules on the LECs.…”

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confidence: 99%

Chemokine CCL2 facilitates ICAM‐1‐mediated interactions of cancer cells and lymphatic endothelial cells in sentinel lymph nodes

Kawai¹,

Kaidoh²,

Yokoyama³

et al. 2009

Cancer Science

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We examined the effects of CCL1, CCL2, CCL12 and CCL21 on the expression of adhesion molecules in cultured human lymphatic endothelial cells using immunohistochemical staining or Western blot analysis. In addition, we investigated whether the expressed adhesion molecule was able to facilitate the attachment of carcinoma cells to the lymphatic endothelial cells as an in vitro micrometastatic model. CCL2 caused a selective and significant expression of ICAM-1 on human lymphatic endothelial cells but CCL1, CCL12 and CCL21 did not. By increasing the stimulation time from 4 to 18 and 48 h, the intensity of immunoreactivity for ICAM-1 was significantly increased in a time-dependent manner up to 18 h. The ICAM-1 mRNA levels were also elevated significantly up to 18 h. The CCL2-mediated immunohistochemical expression of ICAM-1 was dose-dependently increased from 10 pg/mL to 1 ng/mL. The CCL2-mediated expression of ICAM-1 was significantly reduced by neutralization of CCL2 using a specific CCL2 antibody. C hemokines are soluble, small molecular-weight proteins that bind to their cognate G-protein coupled receptors to elicit cellular responses, usually directional migration or chemotaxis.(1,2) Tumor cells secrete and respond to chemokines, which facilitate the tumor growth that is achieved by increased endothelial cell recruitment, subversion of immunological surveillance, and maneuvering of the tumoral leukocyte chemokine profile to skew it (immunoediting) such that the chemokines released enable tumor growth and metastasis to distant sites. Thus, the CXCL12-CXCR4 axis facilitates metastasis to distant organs, and the CCL21-CCR7 pair favors metastasis to lymph nodes. These two chemokine ligand-receptor systems are key mediators of tumor cell metastasis for several malignancies and as such provide key targets for chemotherapy. (2,3) Recently, the concept of sentinel lymph node (SLN), which is the first node in the lymphatic network draining the primary tumor, has been proposed by mapping of regional lymph nodes using radioisotopes or dye. The SLN is the presumptive initial site of lymphatic micrometastasis of carcinoma cells. The clinical importance of SLN has been proven in many breast cancer patients.(4) However, the biological and histological properties of the lymphatic endothelial cells (LECs) in the SLN that interact with micrometastatic carcinoma cells remain unclear. It has also become known that primary tumors influence the microenvironment of tumor tissues before metastasis.(5,6) However, it is unclear which molecules in the premetastatic SLN develop a suitable environment for the micrometastasis that is related to the attachment of carcinoma cells to LECs.Therefore, we have attempted to examine the effects of various kinds of chemokines on the expression of adhesion molecules on cultured human LECs located in the nearest afferent lymph vessels of the SLN, and then investigate whether the expressed adhesion molecules are able to facilitate the attachment of carcinoma cells to the LECs. In addition, we studied th...

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confidence: 99%

Chemokine CCL2 facilitates ICAM‐1‐mediated interactions of cancer cells and lymphatic endothelial cells in sentinel lymph nodes

Kawai¹,

Kaidoh²,

Yokoyama³

et al. 2009

Cancer Science

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“…CCL2 was also upregulated in our model. Researchers have shown that intratumoral injection of CCL2 induces effective interaction between monocytes and endothelial cells in the peritumoral area, accompanied by the upregulation of ICAM-1 [21]. …”

Section: Resultsmentioning

confidence: 99%

VEGF induces expression of Bcl-2 and multiple signaling factors in microvascular endothelial cells in a prostate cancer model

et al. 2009

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Purpose We have previously demonstrated that prostate tumors that highly express Bcl-2 are not only more tumorigenic, but also more angiogenic than low Bcl-2 expressing tumors. Observed increased rates of angiogenesis are likely due to the secretion of multiple factors from the tumor cells. Experimental design Human endothelial cells were subjected to exogenous VEGF or conditioned media from PC-3 cells and assayed by several in vitro systems to better characterize the eVects of tumor microenvironment on endothelial cells. Results VEGF stimulation increased Bcl-2 expression in human microvascular endothelial cells (HMVECs), at least partially through stabilization of Bcl-2 mRNA transcripts, and protected these cells from apoptosis. These effects were mimicked by treatment of HMVECs with conditioned media from cultured PC-3 prostate tumor cells manipulated to overexpress Bcl-2. Through the use of kinase inhibitors and molecular profiling, several distinct pathways were implicated in the regulation of Bcl-2 in HMVECs, including those involving PI3K/AKT, PKC, mTOR, STAT-1, and IL-8, factors associated with tumor survival and growth. Conclusions This study identifies molecular elements of a link between Bcl-2 expression in distinct cell types within a tumor and reaffirms that strategies designed to target Bcl-2 are desirable as they might enhance treatment response through dual effects.

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“…Since surface expression of adhesion molecules on inflammatory cells regulates organ-specific recruitment, cancer immunity against a subcutaneous tumor may differ from that of a tumor in the pancreas, where gut-tropic infiltrating cells mainly play a role. Using this model, we demonstrated that administration of recombinant CCL2 in tumor tissue induced significant recruitment of inflammatory cells, including monocytes and lymphocytes (33). We could not achieve a significant antitumor effect, possibly because CCL2 also enhanced the recruitment of Treg cells, PD-1-positive cells and B7-DCpositive cells in tumor tissue (unpublished data).…”

Section: Introductionmentioning

confidence: 95%

“…Male C57BL/6 mice, 4-5 weeks of age and maintained on standard laboratory chow (Oriental Yeast, Tokyo, Japan), were used for the study. Preparation of cells and the tumor inoculation were performed according to our previous report (32,33). Briefly, under pentobarbital anesthesia, a small left lateral laparotomy was performed and a pellet containing 4x10 5 cells in growth factor-reduced Matrigel (BD Biosciences, Bedford, MA) was injected into the pancreas.…”

Section: Methodsmentioning

confidence: 99%

Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model

Okudaira

Hokari²,

Tsuzuki³

et al. 2009

Int J Oncol

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Abstract. The negative signal provided by interactions of programmed death-1 (PD-1) and its ligands, B7-H1 and B7-DC, has been suggested to play an important role in tumor evasion from host immunity. Pancreas cancer patients with B7-H1 expression have a poor prognosis. B7-H1 blocking has been shown to inhibit the development of a subcutaneous tumor from a pancreas cancer cell line. In this study, we investigated the effects of B7-DC as well as B7-H1 blockade in vivo in a murine pancreatic cancer model. Pancreatic cancer cells (Panc02) were inoculated in the pancreas of C57BL/6 mice. Five weeks later, tumor sizes were measured and the mice bearing appropriate size of tumors received the following treatments. Blocking antibodies against B7-H1 or B7-DC (200 μg) were administered 3 times/week for 3 weeks. Cells infiltrating the tumors were characterized by immunohistochemistry. Effects of antibodies on cytokine and FoxP3 expression were examined by quantitative RT-PCR. In vitro cultured Panc02 cells expressed B7-H1 upon IFN-Á stimulation. However, expression of B7-H1 and B7-DC was found mainly on CD45-positive infiltrating cells and rarely on cancer cells in vivo. Treatment with both antibodies significantly decreased tumor growth in vivo. B7-DC blockade decreased the levels of IL-10 and FoxP3, suggesting that regulatory systems are mainly inhibited at the tumor site. B7-H1 blockade increased the levels of IFN-Á and FoxP3. Collectively, blocking of B7-H1 or B7-DC efficiently induced regression of pre-established pancreatic cancers by upregulating IFN-Á production and down-regulating IL-10 production at the tumor site.

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Effects of Intratumoral Injection of CCL2 on Monocyte–Endothelial Cell Interactions in Mouse Pancreatic Cancer

Cited by 8 publications

References 34 publications

Chemokine CCL2 facilitates ICAM‐1‐mediated interactions of cancer cells and lymphatic endothelial cells in sentinel lymph nodes

Chemokine CCL2 facilitates ICAM‐1‐mediated interactions of cancer cells and lymphatic endothelial cells in sentinel lymph nodes

VEGF induces expression of Bcl-2 and multiple signaling factors in microvascular endothelial cells in a prostate cancer model

Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model

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