Myeloid heme oxygenase‐1 promotes metastatic tumor colonization in mice

Heme oxygenase-1 (HO-1) is a heme degradation enzyme with antioxidant and immune-modulatory functions. HO-1 promotes tumorigenesis by enhancing tumor cell proliferation and invasion. Whether HO-1 has an effect on cancer progression through stromal compartments is less clear. Here we show that the growth of tumor engrafted subcutaneously in syngeneic mice was not affected by host HO-1 expression. However, lung metastasis arisen from subcutaneous tumor or circulating tumor cells was significantly reduced in HO-1^+/− mice comparing to wild type (WT) mice. The reduced lung metastasis was also observed in B6 mice bearing HO-1^+/− bone marrow as comparing to WT chimeras, indicating that HO-1 expression in hematopoietic cells impacts tumor colonization at the metastatic site. Further experiments demonstrated that the numbers of myeloid cells recruited to pulmonary premetastatic niches and metastatic loci were significantly lower in HO-1^+/− mice than in WT mice. Likewise, the extents of tumor cell extravasation and colonization at the metastatic loci in the early phase of metastasis were significantly lower in HO-1^+/− mice. Mechanistic studies revealed that HO-1 impacted chemoattractant-induced myeloid cell migration by modulating p38 kinase signaling. Moreover, myeloid HO-1-induced expressions of vascular endothelial growth factor and interleukin-10 promoted tumor cell transendothelial migration and STAT3 activation in vitro. These data support a pathological role of myeloid HO-1 in metastasis and suggest a possibility of targeting myeloid HO-1 for cancer treatment.     

通讯作者：花宝金(1964-),男,黑龙江人,主任医师,博士研究生导师,研究方向: 中医药防治肿瘤复发转移。稿件联系人：蒋树龙,E-mail:jnsljiang@163.com。联系电话：13506383007。

【】　目的：总结JAK2/STAT3/SOCS3信号通路的作用特点及其与肿瘤转移潜能的最新研究进展。方法：应用PubMed及CNKI期刊全文数据库,以“JAK2、STAT3、SOCS3、肿瘤和信号转导”为关键词,检索2000-01~2013-10的相关文献,共检索到英文文献343篇,中文文献66篇。文献纳入标准：１)JAK2/STAT3/SOCS3信号通路的生物学特征及作用机制;２)JAK2/STAT3/SOCS3信号通路与肿瘤微环境的关系及其与肿瘤侵袭转移之间的内在联系。根据纳入标准符合条件的30篇。结果：JAK2/STAT3信号通路的激活参与了肿瘤发生、发展、侵袭和转移等多个环节;SOCS3负性调控JAK2/STAT3通路,从而抑制肿瘤的增殖和生长;STAT3信号通路的激活促成了肿瘤炎性微环境的形成,参与了肿瘤血管生成、上皮间质转化(EMT)、细胞外基质(ECM)降解等多个环节,在肿瘤的侵袭和转移过程中发挥重要作用。结论：JAK2/STAT3/SOCS3信号通路与肿瘤转移密切相关,针对JAK2/STAT3/SOCS3信号通路多靶点干预是肿瘤防治研究的一个新方向。     

Silencing of SOCS1 in macrophages suppresses tumor development by enhancing antitumor inflammation

Inflammation has been shown to contribute to both tumor development and antitumor immunity. However, conditions determining these opposing effects are not well understood. Suppressor of cytokine signaling 1 (SOCS1) has been shown to play an important role in regulating inflammation and tumor development. It has been reported that silencing of SOCS1 gene in dendritic cells potentiates antitumor immunity, while SOCS1 -deficiency in whole organs except for T and B cells enhances inflammation-mediated colon tumor development. To determine which types of cells are important for the suppression of tumor development by SOCS1 -deficiency, we employed the conditional knockout strategy. SOCS1 gene was deleted in macrophages and neutrophils by crossing SOCS1-flox/flox mice with LysM-cre mice. Resulting conditional knockout (cKO) mice showed enhanced sensitivity to endotoxin shock. SOCS1- cKO mice survived much longer than wild-type mice after B16 melanoma transplantation. Colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) plus dextran sulfate sodium (DSS) was also reduced in SOCS1 -cKO mice. SOCS1 -deficiency in monocytic cells enhanced tumor-killing activity of macrophages and tumor-specific cytotoxic T cell activity. These results suggest that inflammation induced by SOCS1 -deficiency in monocytes potentiates antitumor immune responses rather than tumor-promoting inflammation. ( Cancer Sci 2009; 100: 730–736)     

CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity

Chemokines and chemokine receptors have critical roles in cancer metastasis and have emerged as one of the targeting options in cancer therapy. However, the treatment efficacy on both tumor and host compartments needs to be carefully evaluated. Here we report that targeting CXCR3 decreased tumor cell migration and at the same time improved host anti-tumor immunity. We observed an increased expression of CXCR3 in metastatic tumor cells compared to those from non-metastatic tumor cells. Knockdown (KD) of CXCR3 in metastatic tumor cells suppressed tumor cell migration and metastasis. Importantly, CXCR3 expression in clinical breast cancer samples correlated with progression and metastasis. For the host compartment, deletion of CXCR3 in all host cells in 4T1 mammary tumor model significantly decreased metastasis. The underlying mechanisms involve a decreased expression of IL-4, IL-10, iNOs, and Arg-1 in myeloid cells and an increased T cell response. IFN-γ neutralization diminished the metastasis inhibition in the CXCR3 knockout (KO) mice bearing 4T1 tumors, suggesting a critical role of host CXCR3 in immune suppression. Consistently, targeting CXCR3 using a small molecular inhibitor (AMG487) significantly suppressed metastasis and improved host anti-tumor immunity. Our findings demonstrate that targeting CXCR3 is effective in both tumor and host compartments, and suggest that CXCR3 inhibition is likely to avoid adverse effects on host cells.     

Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway

Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2(+)Ly6C(hi) monocytes. However, the mechanisms driving tumor cell extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2(+) endothelium to increase vascular permeability in?vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2(-/-) mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.     

Emodin suppresses pulmonary metastasis of breast cancer accompanied with decreased macrophage recruitment and M2 polarization in the lungs

Breast cancer is the leading cause of death in female cancer patients due to the lack of effective treatment for metastasis. Macrophages are the most abundant immune cells in the primary and metastatic tumors, and contribute to tumor initiation, progression, and metastasis. Emodin has been found to exert anti-tumor effects through promoting cell cycle arrest and apoptosis, and inhibiting angiogenesis, but its effects on tumor-associated macrophages during cancer metastasis have not been investigated. Mice inoculated with 4T1 or EO771 breast cancer cells orthotopically were treated with Emodin after the primary tumors reached 200 mm³ in size. Primary tumor growth, lung metastasis, and macrophage infiltration in the lungs were analyzed. In vitro experiments were performed to examine the effects of Emodin on macrophage migration and M2 polarization, and the underlying mechanisms. Emodin significantly suppressed breast cancer lung metastasis in both orthotopic mouse models without apparent effects on primary tumors. Reduced infiltration of F4/80+ macrophages and Ym1+ M2 macrophages in lungs was observed in Emodin-treated mice. In vitro experiments demonstrated that Emodin decreased the migration of macrophages toward tumor cell-conditioned medium (TCM) and inhibited macrophage M2 polarization induced by TCM. Mechanistically, Emodin suppressed STAT6 phosphorylation and C/EBPβ expression, two crucial signaling events in macrophage M2 polarization, in macrophages treated with IL-4 or TCM. Taken together, our study, for the first time, demonstrated that Emodin suppressed pulmonary metastasis of breast cancer probably through inhibiting macrophage recruitment and M2 polarization in the lungs by reducing STAT6 phosphorylation and C/EBPβ expression.     

Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon

Intestinal injury or chronic inflammation induce cytokines that promote crypt regeneration and mucosal repair. If excessive or prolonged, such mechanisms may increase colon cancer risk. Factors that terminate or limit cytokine action in intestinal epithelial cells (IEC) may protect against crypt hyperplasia and neoplasia. We hypothesized that suppressor of cytokine signaling-3 (SOCS3) is such a factor. Mice with Vilin-promoter/Cre-recombinase (VC)-mediated IEC-specific SOCS3 gene disruption (VC/HO), WT/HO littermates with floxed but intact SOCS3 genes and VC/WT mice were studied. Colon was examined after acute dextran sodium sulfate (DSS)-induced mucosal injury or after azoxymethane (AOM) and chronic DSS. Signaling pathways were examined in colon, cultured IEC or colon cancer cell lines. VC/HO mice showed no basal phenotype. After acute DSS, VC/HO exhibited enhanced crypt proliferation and crypt hyperplasia and reduced transforming growth factor (TGF) beta expression in colon. Inflammation and mucosal damage were similar across genotypes. Following AOM/DSS, VC/HO mice had increased size, number and load of colonic tumors and increased STAT3 and nuclear factor-kappa B (NF-kappaB) activation in colon. In vitro, SOCS3 overexpression reduced proliferation, IL-6-mediated STAT3 activation and tumor necrosis factor (TNF) alpha-mediated NF-kappaB activation. We conclude that cytokine induction of SOCS3 normally provides an intrinsic mechanism to limit injury-induced crypt hyperproliferation and inflammation-associated colon cancer by regulating both STAT3 and NF-kappaB pathways.     

Dequalinium blocks macrophage-induced metastasis following local radiation

A major therapeutic obstacle in clinical oncology is intrinsic or acquired resistance to therapy, leading to subsequent relapse. We have previously shown that systemic administration of different cytotoxic drugs can induce a host response that contributes to tumor angiogenesis, regrowth and metastasis. Here we characterize the host response to a single dose of local radiation, and its contribution to tumor progression and metastasis. We show that plasma from locally irradiated mice increases the migratory and invasive properties of colon carcinoma cells. Furthermore, locally irradiated mice intravenously injected with CT26 colon carcinoma cells succumb to pulmonary metastasis earlier than their respective controls. Consequently, orthotopically implanted SW480 human colon carcinoma cells in mice that underwent radiation, exhibited increased metastasis to the lungs and liver compared to their control tumors. The irradiated tumors exhibited an increase in the colonization of macrophages compared to their respective controls; and macrophage depletion in irradiated tumor-bearing mice reduces the number of metastatic lesions. Finally, the anti-tumor agent, dequalinium-14, in addition to its anti-tumor effect, reduces macrophage motility, inhibits macrophage infiltration of irradiated tumors and reduces the extent of metastasis in locally irradiated mice. Overall, this study demonstrates the adverse effects of local radiation on the host that result in macrophage-induced metastasis.     

Angiotensin II subtype 1a receptor signaling in resident hepatic macrophages induces liver metastasis formation

Liver metastases from colorectal cancer (CRC) are a clinically significant problem. The renin–angiotensin system is involved in tumor growth and metastases. This study was designed to evaluate the role of angiotensin II subtype receptor 1a (AT1a) in the formation of liver metastasis in CRC. A model of liver metastasis was developed by intrasplenic injection of mouse colon cancer (CMT‐93) into AT1a knockout mice (AT1aKO) and wild‐type (C57BL/6) mice (WT). Compared with WT mice, the liver weight and liver metastatic rate were significantly lower in AT1aKO. The mRNA levels of CD31, transforming growth factor‐ β1 (TGF‐β1), and F4/80 were suppressed in AT1aKO compared with WT. Double immunofluorescence analysis showed that the number of accumulated F4/80⁺ cells expressing TGF‐β1 in metastatic areas was higher in WT than in AT1aKO. The AT1aKO bone marrow (BM) (AT1aKO‐BM)→WT showed suppressed formation of liver metastasis compared with WT‐BM→WT. However, the formation of metastasis was further suppressed in WT‐BM→AT1aKO compared with AT1aKO‐BM→WT. In addition, accumulated F4/80⁺ cells in the liver metastasis were not BM‐derived F4/80⁺ cells, but mainly resident hepatic F4/80⁺ cells, and these resident hepatic F4/80⁺ cells were positive for TGF‐β1. Angiotensin II enhanced TGF‐β1 expression in Kupffer cells. Treatment of WT with clodronate liposomes suppressed liver metastasis by diminishing TGF‐β1⁺F4/80⁺ cells accumulation. The formation of liver metastasis correlated with collagen deposition in the metastatic area, which was dependent on AT1a signaling. These results suggested that resident hepatic macrophages induced liver metastasis formation by induction of TGF‐β1 through AT1a signaling.     

CCL3 and CCL20-recruited dendritic cells modified by melanoma antigen gene-1 induce anti-tumor immunity against gastric cancer ex vivo and in vivo

Background

To investigate whether dendritic cell (DC) precursors, recruited by injection of chemokine ligand 3 (CCL3) and CCL20, induce anti-tumor immunity against gastric cancer induced by a DC vaccine expressing melanoma antigen gene-1 (MAGE-1) ex vivo and in vivo.

Methods

B6 mice were injected with CCL3 and CCL20 via the tail vein. Freshly isolated F4/80^-B220^-CD11c⁺ cells cultured with cytokines were analyzed by phenotype analysis and mixed lymphocyte reaction (MLR). For adenoviral (Ad)-mediated gene transduction, cultured F4/80^-B220^-CD11c⁺ cells were incubated with Ad-MAGE-1. Vaccination of stimulated DC induced T lymphocytes. The killing effect of these T cells against gastric carcinoma cells was assayed by MTT. INF-γ production was determined with an INF-γ ELISA kit. In the solid tumor and metastases model, DC-based vaccines were used for immunization after challenge with MFC cells. Tumor size, survival of mice, and number of pulmonary metastatic foci were used to assess the therapeutic effect of DC vaccines.

Results

F4/80^-B220^-CD11c⁺ cell numbers increased after CCL3 and CCL20 injection. Freshly isolated F4/80^-B220^-CD11c⁺ cells cultured with cytokines were phenotyically identical to typical DC and gained the capacity to stimulate allogeneic T cells. These DCs were transduced with Ad-MAGE-1, which were prepared for DC vaccines expressing tumor antigen. T lymphocytes stimulated by DCs transduced with Ad-MAGE-1 exhibited specific killing effects on gastric carcinoma cells and produced high levels of INF-γ ex vivo. In vivo, tumor sizes of the experimental group were much smaller than both the positive control group and the negative control groups (P < 0.05). Kaplan-Meier survival curves showed that survival of the experimental group mice was significantly longer than the control groups (P < 0.05). In addition, MAGE-1-transduced DCs were also a therapeutic benefit on an established metastatic tumor, resulting in a tremendous decrease in the number of pulmonary metastatic foci.

Conclusions

CCL3 and CCL20-recruited DCs modified by adenovirus-trasnsduced, tumor-associated antigen, MAGE-1, can stimulate anti-tumor immunity specific to gastric cancer ex vivo and in vivo. This system may prove to be an efficient strategy for anti-tumor immunotherapy.     

Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480

STAT3 has important functions in both tumor cells and the tumor microenvironment to facilitate cancer progression. The STAT regulatory kinase Janus-activated kinase (JAK) has been strongly implicated in promoting oncogenesis of various solid tumors, including the use of JAK kinase inhibitors such as AZD1480. However, direct evidence that JAK drives STAT3 function and cancer pathogenesis at the level of the tumor microenvironment is yet to be established clearly. In this study, we show that AZD1480 inhibits STAT3 in tumor-associated myeloid cells, reducing their number and inhibiting tumor metastasis. Myeloid cell-mediated angiogenesis was also diminished by AZD1480, with additional direct inhibition of endothelial cell function in vitro and in vivo. AZD1480 blocked lung infiltration of myeloid cells and formation of pulmonary metastases in both mouse syngeneic experimental and spontaneous metastatic models. Furthermore, AZD1480 reduced angiogenesis and metastasis in a human xenograft tumor model. Although the effects of AZD1480 on the tumor microenvironment were important for the observed antiangiogenic activity, constitutive activation of STAT3 in tumor cells themselves could block these antiangiogenic effects, showing the complexity of the JAK/STAT signaling network in tumor progression. Together, our results indicated that AZD1480 can effectively inhibit tumor angiogenesis and metastasis mediated by STAT3 in stromal cells as well as tumor cells.     

Induction of metastatic potential by TrkB via activation of IL6/JAK2/STAT3 and PI3K/AKT signaling in breast cancer

In metastatic breast cancers, the acquisition of metastatic ability, which leads to clinically incurable disease and poor survival, has been associated with acquisition of epithelial-mesenchymal transition (EMT) program and self-renewing trait (CSCs) via activation of PI3K/AKT and IL6/JAK2/STAT3 signaling pathways. We found that TrkB is a key regulator of PI3K/AKT and JAK/STAT signal pathway-mediated tumor metastasis and EMT program. Here, we demonstrated that TrkB activates AKT by directly binding to c-Src, leading to increased proliferation. Also, TrkB increases Twist-1 and Twist-2 expression through activation of JAK2/STAT3 by inducing c-Src-JAK2 complex formation. Furthermore, TrkB in the absence of c-Src binds directly to JAK2 and inhibits SOCS3-mediated JAK2 degradation, resulting in increased total JAK2 and STAT3 levels, which subsequently leads to JAK2/STAT3 activation and Twist-1 upregulation. Additionally, activation of the JAK2/STAT3 pathway via induction of IL-6 secretion by TrkB enables induction of activation of the EMT program via induction of STAT3 nuclear translocation. These observations suggest that TrkB is a promising target for future intervention strategies to prevent tumor metastasis, EMT program and self-renewing trait in breast cancer.     

STAT3与SOCS3在乳腺癌组织中的表达及生物学行为相关性分析

目的：研究乳腺癌组织中信号转导和转录激活因子3（STAT3）和细胞因子信号转导抑制分子3（SOCS3）的表达与肿瘤分化、浸润、转移的关系。方法：应用组织芯片和免疫组织化学Envision法检测71例乳腺癌组织和41例非癌组织中STAT3、磷酸化STAT3、SOCS3的表达情况及其与临床病理参数的关系。结果：（1）在71例乳腺癌中STAT3、磷酸化STAT3和SOCS3的阳性表达率分别为78.9%、69.0%和29.6%,与对照组比较,差异有统计学意义（P〈0.01,P〈0.01,P〈0.05）;（2）STAT3、磷酸化STAT3表达与乳腺癌的组织学分级、腋窝淋巴结转移、临床分期呈正相关（P〈0.05,P〈0.01）,与患者年龄、瘤体大小和组织学类型无关（P〉0.05）;SOCS3表达与乳腺癌组织学分级、腋窝淋巴结转移呈负相关（P〈0.05）,与患者年龄、组织学类型、瘤体大小和临床分期无关（P〉0.05）;（3）乳腺癌组织中STAT3、磷酸化STAT3表达与SOCS3表达分别呈负相关（P〈0.01）。结论：乳腺癌STAT3、磷酸化STAT3的高表达和SOCS3的缺失表达与肿瘤发生发展、浸润转移密切相关;对其检测有助于判断乳腺癌的恶性程度及生物学行为。     

Increased rejection of primary tumors in mice lacking B cells: inhibition of anti-tumor CTL and TH1 cytokine responses by B cells

We investigated the role of B cells in tumor immunity by studying immune responses of mice genetically lacking B cells to primary tumors. IgM(-/-) B cell-deficient mice (BCDM) exhibited enhanced resistance to 3 histologically diverse syngeneic tumors as compared to the wild-type (WT) mice. EL4 thymoma and MC38 colon carcinoma grew progressively in WT mice, but regressed spontaneously in BCDM whereas growth of B16 melanoma was slowed significantly in BCDM as compared to the WT mice. BCDM exhibited increased T cell infiltration of tumors, higher T(H)1 cytokine response and, in the case of MC38, a higher anti-tumor CTL response. The increased tumor resistance of BCDM did not seem to result from intrinsic changes in their non-B immunocytes because adoptive transfer of WT splenic B cells to BCDM abrogated tumor rejection and resulted in diminished anti-tumor T(H)1 cytokine and CTL responses. Studies involving BCR-transgenic mice indicated that B cells may inhibit anti-tumor T cell responses by antigen-nonspecific mechanisms since neither tumor-specific antibodies nor cognate T:B interactions were necessary for inhibition of tumor immunity by B cells. IFN-gamma secretion in splenocyte:tumor co-cultures of tumor-challenged BCDM was inhibited by WT but not CD40(-/-) B cells indicating that B cells may inhibit anti-tumor T(H)1 cytokine responses in a CD40-dependent manner. Adoptive transfer of CD40(-/-) B cells into BCDM resulted in restored growth of MC38 suggesting additional factors other than CD40 are involved in dampening anti-tumor responses. The effects of B cells on anti-tumor response warrant further study.     

Relationship between HER2 and JAK/STAT-SOCS3 signaling pathway and clinicopathological features and prognosis of ovarian cancer

Objective: The study aims to explore the relationship between expressions of HER2 and JAK/STAT3-SOCS3 signaling pathway and clinicopathological features and prognosis of ovarian cancer (OC).Methods: A total of 136 OC patients were collected. Immunohistochemistry was applied to measure the expressions of STAT3, p-STAT3, SOCS3, HER2 and p-HER2 in the tumor tissues and adjacent normal tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expressions of HER2, SOCS3 and STAT3 and western blotting was applied for protein expressions of HER2, p-HER2, SOCS3, STAT3 and p-STAT3 in the tumor tissues and adjacent normal tissues. Flow cytometry was used for the cell apoptosis in the blank, afatinib (A), ruxolitinib (R) and afatinib + ruxolitinib (A + R) groups. Follow-up was performed to explore relationship of HER2, SOCS3, and STAT3 expressions with survival time of OC patients.Results: HER2, p-HER2, STAT3, and p-STAT3 expressions were higher while SOCS3 expression was lower in the tumor tissues. The positive expressions of STAT3, HER2, p-HER2 and p-STAT3 were lower while the positive expression of SOCS3 was higher in the adjacent normal tissues. The expressions of HER2, SOCS3, and p-STAT3 were associated with clinical stage and lymph node metastasis (LNM), and STAT3 expression has correlation with histological grade and LNM. The mRNA and protein expressions of HER2, STAT3 and p-STAT3 in the tumor tissues were higher than those in the adjacent normal tissues, but SOCS3 expression was significantly decreased. The positive expressions of HER2, p-HER2 and STAT3, the negative expression of SOCS3 and pathological stages were important risk factors for the prognosis of patients with OC.Conclusion: Our study showed that the expressions of HER2, STAT3, and SOCS3 are associated with the progression of OC, and higher expressions of HER2 and STAT3 and lower expression of SOCS3 predict poor prognosis of OC.     

Induction of proinflammatory mediators by CHI3L1 is reduced by chitin treatment: decreased tumor metastasis in a breast cancer model

Disseminated metastasis accounts for over 90% of breast cancer deaths. Recently, elevated serum levels of a glycoprotein known as chitinase-3 like-protein-1 (CHI3L1) has been correlated with poor prognosis and shorter survival of patients with metastatic breast cancer. In this study, we show that there are increased levels of CHI3L1 in plasma of tumor-bearing mice and that both tumor cells and immune cells express and secrete CHI3L1. However, the biological and physiological functions of CHI3L1 are still unclear. We demonstrate that while CHI3L1 has an inhibitory role in the expression of interferon-gamma (IFN-γ), CHI3L1 up-regulates pro-inflammatory mediators, C-chemokine ligand 2 (CCL2), chemokine CX motif ligand 2 (CXCL2) and matrix metalloproteinase-9 (MMP-9) all of which contribute to tumor growth and metastasis. We found that in vitro inhibition of CHI3L1 by siRNA suppressed the production of CCL2, CXCL2 and MMP-9 by macrophages. In vivo treatment of mammary tumor-bearing mice with chitin (β-(1-4)-poly-N-acetyl D-glucosamine), a TH(1) adjuvant and a ligand for CHI3L1, promoted immune effector functions with increased production of IFN-γ and decreased CCL2, CXCL2 and MMP-9 expression. In vivo administration of chitin to mammary tumor-bearing mice significantly decreased lung metastasis. These studies show that CHI3L1 plays a role in tumor progression and that chitin can inhibit the pleiotropic effects of CHI3L1 giving support to the idea that CHI3L1 is a useful therapeutic target for treatment of breast cancer.     

Up-regulation of CC chemokine,CCL3L1, and receptors,CCR3, CCR5 in human glioblastoma that promotes cell growth

Human CC ligand 3-like protein 1 (CCL3L1), a member of the CC chemokine family, that induces MCP1 and RANTES, exhibits a variety of proinflammatory activities including chemotaxis, and functional and proliferative activation of leukocytes, lymphocytes and macrophages. Its signal is transmitted through transmembrane receptors, CC chemokine receptors, CCR1, CCR3 and CCR5. To examine gene expression of chemokine, CCL3L1, and its receptors, CCR1, CCR3 and CCR5, we analyzed tumor tissues from 21 patients with several types of primary gliomas. CCL3L1, CCR3 and CCR5 gene exhibited over-expression in 70% (7/10), 60% (6/10), and 60% (6/10) of glioblastoma, in comparison with lower frequencies seen in lower-grade gliomas. Transfection of CCL3L1-expression vector to glioblastoma cell line enhanced proliferation of the tumor cells. These data suggest that increased expression of the CCL3L1, CCR3 and CCR5 chemokine-receptors system is involved in brain tumorigenesis, especially in the progression of glioblastoma.     

Spontaneous regression of lung metastasis in the absence of tumor necrosis factor receptor p55

In order to clarify the roles of tumor necrosis factor (TNF)-alpha in lung metastasis, we injected Renca cells intravenously into TNF receptor p55-deficient (TNF-Rp55 KO) and wild-type (WT) mice. Microscopic and macroscopic metastasis foci appeared in lungs at 7 and 14 days after the tumor injection, respectively. Moreover, metastasis foci expanded at similar rates in both WT and TNF-Rp55 KO mice until 21 days, and lungs were occupied with metastasis foci. However, later than 21 days after the injection, metastasis foci spontaneously regressed in TNF-Rp55 KO mice, whereas WT mice exhibited a progressive growth of metastasis foci. Moreover, metastasis foci remained reduced sizes in TNF-Rp55 KO mice even at 26 days, when all WT mice died with lungs filled with metastasis foci. Later than 21 days after the tumor injection, the number of apoptotic tumor cells was increased in TNF-Rp55 KO mice. In contrast, neovascularization was less evident in TNF-Rp55 KO than WT mice, with depressed hepatocyte growth factor (HGF) gene in TNF-Rp55 KO mice at 21 days after the tumor injection. Thus, TNF-Rp55-mediated signals can maintain tumor neovascularization at least partly by inducing HGF expression, and eventually support lung metastasis process.