人胃癌细胞株裸鼠皮下移植瘤模型的建立及其生物学特性

目的初步建立不同浓度下制备人胃癌细胞株BGC-823裸鼠皮下移植瘤模型,观察其生物学特性。方法培养人胃癌细胞系BGC-823细胞,并分别以四个浓度皮下注射于裸鼠腋下每只0.2 mL。根据BGC-823细胞注射浓度将40只裸鼠随机分为四组：组一5×107个活细胞/mL（n=10）;组二1×107个活细胞/mL（n=10）;组三1×106个活细胞/mL（n=10）;组四1×105个活细胞/mL（n=10）。观察各组裸鼠摄食、活动情况、精神状态、死亡率、成瘤时间、成瘤率、肿瘤生长情况,采用免疫组化法检测肿瘤微血管密度。结果各组裸鼠摄食、精神情况正常,无死亡现象。除组四1×105个活细胞/mL浓度组成瘤率为0%外,其余各组成瘤率均为100%,瘤体出现时间在3～7 d,肿瘤血管密度MVD平均为：（123.26±31.57）个/mm2。结论初步建立了人胃癌裸鼠皮下移植瘤模型及建立此细胞系模型的最低浓度。为胃癌的进一步研究奠定了基础。     

Teratocarcinoma cell MHC antigen expression is regulated in vitro by a soluble noninterferon factor

The 402AX murine teratocarcinoma is a spontaneous testicular tumor of 129 (H-2b) origin which does not express MHC encoded antigens. Rejection of this tumor is immunologically mediated and the tumor cells are induced in vivo to synthesize H-2b antigens when passaged in genetically resistant host mice. The present studies demonstrate that serum from tumor primed genetically resistant host mice can induce tumor cell MHC antigen expression in vitro as measured by indirect immunofluorescence using monoclonal antibodies. The inducing factor is specific for 402AX tumor cells and is not interferon as shown by the lack of response of the 402AX tumor to gamma interferon, and the absence of significant interferon activity in inducer serum. These studies demonstrate another factor independent of interferon that can induce MHC class I antigen expression on tumor cells.     

Effect of human lymphoblastoid interferon on human yolk sac tumors in nude mice

The effect of human lymphoblastoid interferon on the growth of human tumors heterotransplanted into nude mice was examined. The human tumor lines examined, named YST-1, YST-2 and YST-3, were derived from yolk sac tumors of the ovary. Daily intraperioneal injection of 3 X 10(4) U interferon per mouse for 14 days did not inhibit the growth of any of these three human tumor lines. A close correlation was observed between the tumor volume and the level of alpha-fetoprotein in sera of mice bearing the YST-1 tumor (r = 0.55) or YST-2 tumor (r = 0.70). No histological differences were detected between tumor cells of interferon-treated and control mice. Tumor-bearing mice treated with interferon showed no marked weight loss.     

Tumor reactivity of immune T cells in short-term culture

 The adoptive transfer of immune T cells is capable of mediating the regression of established neoplasms in a variety of animal tumor models. The antitumor activity is invariably proportional to the number of cells transferred, thus methods to expand immune cell number while maintaining therapeutic efficacy have been extensively investigated. Here we demonstrate that a short-term culture of immune T cells can amplify the T cell number and enhance the therapeutic reactivity against established pulmonary tumor, while maintaining immunological specificity. In contrast, the therapeutic reactivity of immune T cells against established subcutaneous tumor is diminished by short-term culture. While cultured immune T cells are not cytotoxic in a 4-h Cr-release assay, they do specifically secrete interferon γ upon stimulation with tumor cells. T cells cultured after a single exposure to tumor are even more active against pulmonary tumor than T cells cultured from mice immunized repeatedly. This culture system can rapidly induce T cell proliferation and differentiation into mature effector cells, and the resulting cells demonstrate an enhanced ability to treat visceral metastases, but a decreased ability to treat subcutaneous tumor. Thus T cells cultured after a single exposure to tumor represent an ideal population of cells for use in human adoptive immunotherapy trials. Received: 18 July 1996 / Accepted: 27 September 1996     

Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus

Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.     

Enhancement by interferon of natural killer cell activity in mice.

Injection of mice with several interferon inducers, Newcastle Disease virus, polyinosinic-polycytidylic acid and tilorone resulted in an increase in spleen cell cytotoxicity for ⁵¹chromium-labeled mouse YAC tumor target cells in 4-hr in vitro assays. This increase in spleen cell cytotoxicity was abrogated by injection of mice with potent anti-mouse interferon globulin. Inoculation of mice with mouse interferon (but not human leucocyte or mock interferon preparations) also resulted in a marked enhancement of spleen cell cytotoxicity. The extent of enhancement of spleen cell cytotoxicity was directly proportional to the amount of interferon injected and a significant increase was observed after inoculation of as little as 10³ to 10⁴ units of interferon. An effect could be detected as soon as 1 hr after injection of interferon. The increase of spleen cell cytotoxicity after inoculation of an interferon inducer was not due to a localization and accumulation of cytotoxic cells in the spleen but reflected a general increase in cytotoxic cell activity in various lymphoid tissues (except the thymus). The splenic cytotoxic cells from interferon or interferon-inducer-injected mice had the characteristics of natural killer (NK) cells since (i) interferon enhanced spleen cell cytotoxicity in athymic (nu/nu) nude mice, (ii) classical spleen cell fractionation procedures by nylon wool columns, anti-Thy 1.2 serum plus complement, anti-Ig columns, and depletion of FcR+ rosette-forming cells, failed to remove the effector cells generated in vivo or in vitro. Therefore like NK cells, interferon-induced cytotoxic cells lack the surface markers of mature T and B lymphocytes, are not adherent, and are devoid of avid Fc receptors. Furthermore like NK cells, the spleen cells from interferon-treated mice lysed various target cells (known for their sensitivity to NK cells) without H-2 or species restriction. Incubation in vitro of normal spleen cells with interferon also resulted in an increase in cytotoxicity for YAC tumor cells. We conclude that interferon acts directly on NK cells and enhances the inherent cytotoxic activity of these cells.     

人EGFR显性负性突变体抑制胃癌细胞促血管形成能力

目的探讨人表皮生长因子显性负性突变体(dominant negative epidermal growth factor receptor,DNEGFR))对胃癌细胞促血管形成能力的影响及其分子机制,并检测其对裸鼠皮下移植瘤生长的影响。方法选用2株人胃癌细胞,分为如下6组:SGC-7901及NCI-N87细胞未转染组(US组,UN组),SGC-7901及NCI-N87细胞pEGFP-N1质粒转染组(ES组,EN组),SGC-7901及NCI-N87细胞pEGFPN1-DNEGFR质粒转染组(DS组,DN组)。采用人脐静脉内皮细胞(humanumbilical vein endothelial cell,HUVEC)管腔结构形成实验检测体外促血管形成能力,采用酶联免疫吸附测定法(enzyme-linked immunosorbent assay,ELISA)测定细胞培养液中血管内皮生长因子(vascular endothelial growth factor,VEGF)的水平,建立人胃癌细胞裸鼠移植瘤模型,标本微血管密度(microvessel density,MVD)检测体内促血管形成能力,标本体积检测其对裸鼠皮下移植瘤生长的影响。结果转染pEGFPN1-DNEGFR质粒的人胃癌细胞株出现HUVEC管腔结构形成抑制,培养液中VEGF水平降低,MVD计数降低,裸鼠皮下移植瘤体积变小。结论 DNEGFR可能通过下调VEGF分泌抑制胃癌细胞体外及裸鼠体内促血管形成能力,最终抑制裸鼠皮下移植瘤生长。     

Irradiated tumor cells adenovirally engineered to secrete granulocyte/macrophage-colony-stimulating factor establish antitumor immunity and eliminate pre-existing tumors in syngeneic mice

The specific aim of this study was to examine the prophylactic as well as the therapeutic efficacies of irradiated mouse CT26 colon cancer cells, infected with recombinant adenoviruses harboring cDNAs specific for granulocyte macrophage-colony-stimulating factor (GM-CSF), interferon (IFN-γ) and monocyte chemotactic protein1 (MCP-1). Results showed that tumor cells secrete the respective cytokines for several days after infection and subsequent irradiation. Vaccination with irradiated GM-CSF-secreting CT26 cells protected 90% of syngeneic mice challenged with live parental cells. On the other hand, vaccination with irradiated IFNγ or MCP-1-secreting CT26 cells totally failed to protect mice from tumor development after challenge with parental cells. None of the tumor-free mice initially vaccinated with irradiated GM-CSF-producing CT26 cells developed tumor upon repeated challenge with parental cells during the entire observation period. The establishment of specific and long-lasting antitumor immunity following vaccination with GM-CSF-producing tumor cells requires the simultaneous presence of GM-CSF and tumor antigen at the vaccine site. Depletion of CD8⁺ cells, but not CD4⁺ cells, blocked the vaccine efficacy of GM-CSF-producing tumor cells. Subcutaneous injection of irradiated GM-CSF-producing CT26 cells also effectively prevented the growth of a small load of parental tumor that was implanted 3 days earlier or the development of metastatic foci in the lung from intravenously injected parental cells either 7 days before or 3 days after vaccination. Our data thus show that, in these experimental tumor models, subcutaneous injection of irradiated tumor cells adenovirally, transduced with the GM-CSF gene leads not only to prevention of growth of subsequently implanted tumor but also to elimination of pre-existing and metastatic tumors.     

Effect of human interferon β gene transfer upon human glioma, transplanted into nude mouse brain, involves induced natural killer cells

We investigated the immunological responses induced by human interferon β (IFNβ) gene transfer in human gliomas produced in the brains of nude mice. A suspension of human glioma U251-SP cells was injected into the brains of nude mice. The IFNβ gene was transferred by intratumoral injection with cationic liposomes or cationic liposomes associated with anti-glioma monoclonal antibody (immunoliposomes). When intratumoral injection of liposomes or immunoliposomes containing the human IFNβ gene was performed every second day for a total of six injections, starting 7 days after tumor transplantation, complete disappearance of the tumor was observed in six of seven mice that had received liposomes and in all seven mice receiving immunoliposomes. In addition, experimental gliomas injected with immunoliposomes were much smaller than those injected with ordinary liposomes following delayed injections beginning 14 days after transplantation. An immunohistochemical study of the treated nude mouse brains revealed a remarkable induction of natural killer (NK) cells expressing asialoGM1 antigen. To investigate the significance of NK cells in the antitumor effect, we injected liposomes or immunoliposomes containing the human IFNβ gene into tumors in nude mice depleted of NK cells by irradiation and anti-asialoGM1 antibody administration. The antitumor effect of the liposomes or immunoliposomes was abolished. Subsequent subcutaneous glioma challenge of the nude mice after intracerebral tumor implantation and gene transfer resulted in no subcutaneous tumor growth. These results suggest that the induction of NK cells is important in the cytocidal effect of liposomes or immunoliposomes containing the human IFNβ gene upon experimental gliomas. Received: 10 February 1998 / Accepted: 1 September 1998     

Endogenous type I interferons as a defense against tumors

We have reviewed the experimental results which indicate that endogenous type I interferon (IFN) present either constitutively or possibly induced by the tumor plays an important role in limiting the development of transplantable tumors in mice. Thus, treatment with potent polyclonal neutralizing antibodies to IFN alpha/beta markedly enhanced the subcutaneous growth, invasiveness and metastases of xenogeneic tumor cells (uninfected or infected with RNA or DNA viruses) in athymic nude mice; enhanced the intraperitoneal transplantability of six different syngeneic murine tumors in three strains of immunocompetent mice; and completely abrogated the resistance of allogeneic C57Bl/6 (H-2(b)) or C3H (H-2(k)) mice to the multiplication of Friend erythroleukemia cells (H-2(d)) in the liver and spleen resulting in the death of most mice. The mechanisms by which mice respond to the injection of relatively few tumor cells appear to be multiple, to depend on the site of tumor growth, to occur early and prior to an immunologic response. Endogenous type I IFN appears to constitute an essential component of these defense mechanisms enabling the host to restrict tumor growth.     

In vivo antitumor effects of murine interferon- γ -inducing factor/interleukin-18 in mice bearing syngeneic Meth A sarcoma malignant ascites

Interferon-γ-inducing factor/interleukin-18 is a novel cytokine that reportedly augments natural killer (NK) activity in human and mouse peripheral blood mononuclear cell cultures in vitro and has recently been designated IL-18. In this study, IL-18 exhibited significant antitumor effects in BALB/c mice challenged intraperitoneally (i.p.) with syngeneic Meth A sarcoma when administered i.p. on days 1, 2 and 3 after challenge. Intravenous (i.v.) administration also induced antitumor effects in the tumor-bearing mice; however, subcutaneous (s.c.) administration did not. When mice were twice pretreated with 1 μg IL-18 3 days and 6 h before tumor challenge, all mice survived whereas control mice died within 3 weeks of challenge. Inhibitory effects on Meth A cell growth in vitro were not observed with either IL-18 or interferon γ. The effects of IL-18 pretreatment were abrogated by abolition of NK activity after mice had been injected with anti-asialo GM1 antibody 48 h before and, 24 h and 72 h after tumor challenge. Mice pretreated with IL-18 and surviving tumor challenge resisted rechallenge with Meth A cells but could not reject Ehrlich ascites carcinoma, and spleen cells from the resistant mice, but not control mice, exhibited cytotoxic activity against Meth A cells in vitro after restimulation with mitomycin C-treated Meth A cells for 5 days. The effector cells in the spleen cell preparations from resistant mice appear to be CD4⁺ cells because cytolytic activity was significantly inhibited after depletion of this subset by monoclonal antibodies and complement. In conclusion, IL-18 exhibits in vivo immunologically (primarily NK) mediated antitumor effects in mice challenged with syngeneic Meth A sarcoma and induces immunological memory and the generation of cytotoxic CD4⁺ cells. Received: 17 September 1996 / Accepted: 8 November 1996     

Involvement of p38alpha mitogen-activated protein kinase in lung metastasis of tumor cells

To study the role of p38 mitogen-activated protein kinase (p38) activity during the process of metastasis, p38alpha(+/-) mice were subjected to an in vivo metastasis assay. The number of lung colonies of tumor cells intravenously injected in p38alpha(+/-) mice was markedly decreased compared with that in wild-type (WT) mice. On the other hand, the time-dependent increase in tumor volume after subcutaneous tumor cells transplantation was comparable between WT and p38alpha(+/-) mice. Platelets of p38alpha(+/-) mice were poorly bound to tumor cells in vitro and in vivo compared with those of WT mice. E- and P-selectin mRNAs were markedly induced in the lung after intravenous injection of tumor cells. However, the induction of these selectin mRNAs in p38alpha(+/-) mice was weaker than that in WT mice. Furthermore, the resting expression levels of E-selectin in lung endothelial cells and P-selectin in platelets of p38alpha(+/-) mice were suppressed compared with those of WT mice. The number of tumor cells attached on lung endothelial cells of p38alpha(+/-) mice was significantly reduced compared with that of WT mice. The transmigrating activity of tumor cells through lung endothelial cells of p38alpha(+/-) mice was similar to that of WT mice. These results suggest that p38alpha plays an important role in extravasation of tumor cells, possibly through regulating the formation of tumor-platelet aggregates and their interaction with the endothelium involved in a step of hematogenous metastasis.     

Sensitivity of mice to systemic hyperthermia: effect of the transplantation of ascites tumor cells modified by preheating, and by an injection of CDDP or interferon

Effects of preheating and injection of cis-DDP (CDDP) or interferon on tumor-induced sensitization to systemic hyperthermia (SH) was investigated in mice. LD50 of SH at 42.0 +/- 0.2 degrees C (core body temperature) was 43 min in normal mice and 8 min in mice which were i.p. transplanted with FMA3 cells at a dose of 10(5) one day before. In mice which had received the SH for 10 min one hour before, one hour after or one day before the transplantation, LD50 of the SH one day after the transplantation was 41, 35 and 22 min, respectively. An injection of CDDP given i.p. at a dose of 4 mg/kg one day after the transplantation, which was effective to kill about 99% of the tumor cells, did not change the course of thermosensitization after the transplantation. An i.p. injection of mouse interferon did not change the thermosensitivity of normal mice, but greatly suppressed the thermosensitizing effect of tumor cells when it was given one day before the transplantation.     

Long-term cultured human neural stem cells undergo spontaneous transformation to tumor-initiating cells

In this report, we describe the spontaneous malignant transformation of long-term cultured human fetal striatum neural stem cells (hsNSCs, passage 17). After subcutaneous transplantation of long-term cultured hsNSCs into immunodeficient nude mice, 2 out of 15 mice formed xenografts which expressed neuroendocrine tumor markers CgA and NSE. T1 cells, a cell line that we derived from one of the two subcutaneous xenografts, have undergone continuous expansion in vitro. These T1 cells showed stem cell-like features and expressed neural stem cell markers nestin and CD133. The T1 cells were involved in abnormal karyotype, genomic instability and fast proliferation. Importantly, after long-term in vitro culture, the T1 cells did not result in subcutaneous xenografts, but induced intracranial tumor formation, indicating that they adjusted themselves to the intracranial microenvironment. We further found that the T1 cells exhibited an overexpressed level of EGFR, and the CD133 positive T1 cells showed a truncation mutation in the exons 2-7 of the EGFR (EGFRvIII) gene. These results suggest that continuous expansion of neural stem cells in culture may lead to malignant spontaneous transformation. This phenomenon may be functionally related to EGFR by EGFRvIII gene mutation.     

Angiopoietin decoy secreted at tumor site impairs tumor growth and metastases by inducing local inflammation and altering neoangiogenesis

The extracellular domain of the receptor tyrosine kinase Tie2/TEK (exTEK) has been used as an angiopoietin decoy to study the role of angiopoietins in the tumor–host interactions, using a syngeneic model of experimental metastases and subcutaneous tumor. Soluble exTEK secreted by transfected tumor cells inhibited HUVECs from forming tubes in Matrigel. ExTEK-transfected C26 colon carcinoma and TS/A mammary tumor cells displayed reduced growth rate when injected subcutaneously, and reduced ability to form experimental metastases when injected intravenously. Immunohistochemical analysis of tumors and metastases showed increased leukocytes infiltration and signs of inflammation in exTEK-secreting compared to parental tumor, as well as impairment in neo-vessel growth and organization. However, while neoangiogenesis eventually rescued in the subcutis, it failed to organize in the experimental metastases of exTEK-secreting tumor, contributing to the hampering of metastatic growth and to increased mice survival. The reactive infiltrate of C26TEK contained a different percentage of leukocytes and was responsible for the tumor inhibition. In fact, leukopenia induced by -irradiation of recipient mice or injection into interferon gamma (IFN-) gene knockout (GKO) mice resulted in reduced mouse survival and an increased number of lung metastases. On the other hand, interleukin (IL)-12 treatment prolonged the survival of mice bearing subcutaneous C26TEK but not of those bearing lung metastases, suggesting that IL-12 could exert further antiangiogenic effects at the site where the tumor can restore neoangiogenesis. These results show in vivo that reduced angiopoietin availability at the tumor site induces a local inflammatory response and impairment of neoangiogenesis which act synergistically to limit tumor growth and metastasis.Abbreviations AEC amino-ethylcarbazole - ELISA enzyme-linked immunosorbent assay - HRP horseradish peroxidase - HUVEC human umbilical vascular endothelial cell - i.v. intravenous - s.c. subcutaneous - TBS Tris-HCl buffered solution     

Initial steps in lymph node metastasis formation in an experimental system: possible involvement of recognition by macrophage C-type lectins

 We used histological observations and experiments with fluorescent cell tracers to investigate the roles of tissue macrophages in recognition through a galactose/N-acetylgalactosamine-specific C-type lectin (mMGL) in lymph node metastasis formation by mouse ovarian tumor OV2944-HM-1 (HM-1) cells. Lymph node metastasis from subcutaneous sites was shown to be initiated by the entry of tumor cells into the subcapsular sinus of lymph nodes where mMGL-positive cells were mainly located. To investigate whether mMGL-positive cells contributed to host resistance against lymph node metastasis, we repeatedly treated mice bearing transplanted tumors with an mMGL-blocking monoclonal antibody that was known to inhibit mMGL binding to its ligands. The number of HM-1 cells recovered from lymph nodes 2 weeks after subcutaneous injections was significantly greater when the mice were treated with the blocking anti-mMGL antibody. These results suggested that mMGL-positive macrophages contributed to the host's defense against lymph node metastasis. Received: 30 July 1999 / Accepted: 1 November 1999     

Chronic alcohol consumption enhances myeloid-derived suppressor cells in B16BL6 melanoma-bearing mice

We previously found that chronic alcohol consumption decreases the survival of mice bearing subcutaneous B16BL6 melanoma. The underlying mechanism is still not completely understood. Antitumor T cell immune responses are important to inhibiting tumor progression and extending survival. Therefore, we examined the effects of chronic alcohol consumption on the functionality and regulation of these cells in C57BL/6 mice that chronically consumed 20% (w/v) alcohol and subsequently were inoculated subcutaneously with B16BL6 melanoma cells. Chronic alcohol consumption inhibited melanoma-induced memory T cell expansion and accelerated the decay of interferon (IFN)-γ producing T cells in the tumor-bearing mice. Foxp3⁺CD4⁺CD25⁺ regulatory T cells were not affected; however, the percentage of myeloid-derived suppressor cells (MDSC) was significantly increased in the peripheral blood and spleen. T cell proliferation as determined by carboxyfluorescein succinimidyl ester labeling experiments in vitro was inhibited by alcohol consumption relative to control water-drinking melanoma-bearing mice. Collectively, these data show that chronic alcohol consumption inhibits proliferation of memory T cells, accelerates the decay of IFN-γ producing CD8⁺ T cells, and increases MDSC, all of which could be associated with melanoma progression and reduced survival.     

Erratum to: Chronic alcohol consumption enhances myeloid-derived suppressor cells in B16BL6 melanoma-bearing mice

We previously found that chronic alcohol consumption decreases the survival of mice bearing subcutaneous B16BL6 melanoma. The underlying mechanism is still not completely understood. Antitumor T cell immune responses are important to inhibiting tumor progression and extending survival. Therefore, we examined the effects of chronic alcohol consumption on the functionality and regulation of these cells in C57BL/6 mice that chronically consumed 20% (w/v) alcohol and subsequently were inoculated subcutaneously with B16BL6 melanoma cells. Chronic alcohol consumption inhibited melanoma-induced memory T cell expansion and accelerated the decay of interferon (IFN)-γ producing T cells in the tumor-bearing mice. Foxp3⁺CD4⁺CD25⁺ regulatory T cells were not affected; however, the percentage of myeloid-derived suppressor cells (MDSC) was significantly increased in the peripheral blood and spleen. T cell proliferation as determined by carboxyfluorescein succinimidyl ester labeling experiments in vitro was inhibited by alcohol consumption relative to control water-drinking melanoma-bearing mice. Collectively, these data show that chronic alcohol consumption inhibits proliferation of memory T cells, accelerates the decay of IFN-γ producing CD8⁺ T cells, and increases MDSC, all of which could be associated with melanoma progression and reduced survival.     

G-CSF stimulates angiogenesis and promotes tumor growth: potential contribution of bone marrow-derived endothelial progenitor cells

Solid tumors require neovascularization for their growth. Recent evidence indicates that bone marrow-derived endothelial progenitor cells (EPCs) contribute to tumor angiogenesis. We show here that granulocyte colony-stimulating factor (G-CSF) markedly promotes growth of the colon cancer inoculated into the subcutaneous space of mice, whereas G-CSF had no effect on cancer cell proliferation in vitro. The accelerated tumor growth was associated with enhancement of neovascularization in the tumor. We found that bone marrow-derived cells participated in new blood vessel formation in tumor. Our findings suggest that G-CSF may have potential to promote tumor growth, at least in part, by stimulating angiogenesis in which bone marrow-derived EPCs play a role.     

TWEAK mediates anti-tumor effect of tumor-infiltrating macrophage

TWEAK induces diverse cellular responses, including pro-inflammatory chemokine production, migration, proliferation, and cell death through the TWEAK receptor, Fn14. In the present study, we examined the effect of TWEAK or Fn14 expression in tumor cells on tumor outgrowth in vivo. Administration of neutralizing anti-TWEAK mAb significantly reduced the frequency of tumor rejection and shortened the survival of mice intraperitoneally inoculated with TWEAK-sensitive Fn14-expressing tumor cells. Moreover, anti-TWEAK mAb treatment promoted the subcutaneous growth of TWEAK-sensitive Fn14-expressing tumor cells, and this promotion was abolished by the inhibition of macrophage infiltration but not NK cell depletion. In contrast, administration of anti-TWEAK mAb had no apparent effect on the growth of TWEAK-resistant tumor cells, even if tumor cells expressed Fn14. On the other hand, TWEAK expression in tumor cells had no significant effect on subcutaneous tumor growth. These results indicate that TWEAK mediates anti-tumor effect of macrophages in vivo.