Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice

Bone marrow stroma produces positive and negative growth regulators which constitute the hematopoietic microenvironment. As many tumors metastasize to the bones, these regulators may also influence tumor growth. Hematopoietic cytokines may indeed exert both positive and negative effect on tumor growth. We report that, when mixed with tumor cells. adherent bone marrow cells inhibit primary tumor growth and metastases formation in mice transplanted with Lewis lung carcinoma or B16 melanoma. Peritoneal macrophages or lymph node cells did not exert any influence. The tumor inhibition was apparently due to soluble factor(s) released by marrow stromal cells. In cocultures with B16 melanoma cells, adherent bone marrow cells exerted a significant antiproliferative effect which was increased by previous culture of the bone marrow cells with granulocyte-macrophage colony-stimulating factor but not with macrophage colony-stimulating factor. Neither neutralizing antibodies against tumor necrosis factor-alpha, transforming growth factor-beta or interferon alpha/beta nor addition of Escherichia coli lipopolysaccharide to generate inflammatory cytokines could affect the antiproliferative effect of bone marrow stromal cells. The bone marrow stroma factor(s) which inhibit tumor growth might, therefore, be a novel growth regulator.     

Efficacy of tumor cell vaccine after incorporating monophosphoryl lipid A (MPL) in tumor cell membranes containing tumor-associated ganglioside

Murine B16 melanoma expresses the ganglioside. GM₃. GM₃ shed from tumor cells is immunosuppressive and promotes tumor growth¹. Reduction or elimination of the shed GM₃ could be therapeutic, and the anti-GM₃ antibodies may reduce and clear the shed ganglioside. To test this hypothesis, mice were challenged with tumor cells, with or without inducing anti-GM₃ antibody response. Since gangliosides are poor immunogens and T-cell independent antigens, an adjuvant (monophosphoryl lipid A (MPL), a non-toxic lipid A ofSalmonella), directed against B-cells, was employed. MPL was incorporated onto liposomes and into the surface membrane of B16 mouse melanoma cells; both are rich in GM₃. C57BL/6J mice immunized with MPL-liposomes or MPL-B16 cells responded with elevated levels of anti-GM₃ IgM. Non-immunized mice or mice immunized with B16 cells alone or ganglioside GM₃ alone (without MPL) elicited poor anti-GM₃ IgM response, confirming the GM₃'s immunologic crypticity and MPL's immunopotentiating effect. MPL's immunopotentiating effect was improved by coupling it to melanoma cell membranes C57BL/6J mice were immunized with irradiated B16 alone or MPL alone or MPL-conjugated irradiated B16. After three weekly immunizations, each mouse received a challenge dose of viable syngeneic B16. Neither MPL alone nor B16 alone had a significant effect on tumor growth or host survival; however, administration of MPL-conjugated B16 cells significantly prevented tumor growth and prolonged survival. Our results indicate that MPL-incorporated B16 cells augment the anti-GM₃ IgM response, which may reverse GM₃-induced immunosuppression by eliminating tumor-derived GM₃, and restore immunocompetence.     

darbufelone对胃癌SGC-7901细胞裸鼠移植瘤血管生成的影响

目的观察环氧合酶-2／5-脂氧合酶双重抑制剂darbufelone对人胃癌皮下移植瘤血管生成的影响,并初步探讨其机制。方法建立裸鼠实体瘤模型,随机分为darbufelone组和对照组,darbufelone及生理盐水分别连续灌服4周。测量肿瘤质量、体积,计算抑瘤率;免疫组化检测CD34并计算微血管密度;RT—PCR法及Western blot法分析移植瘤组织中MMP-9、VEGF的表达。结果darbufelone可明显抑制裸鼠移植瘤的生长,质量抑瘤率为58．42％,体积抑瘤率为67．13％。darbufelone组的微血管密度（MVD）（15．36±0．30）明显低于对照组（29．47±0．63）（P〈0．05）;darbufelone组肿瘤组织中VEGF及MMP-9在基因水平及蛋白水平的表达（P〈0．05）。结论darbufelone能有效抑制裸鼠移植瘤的生长,减少移植瘤组织中VEGF及MMP-9的表达,抑制肿瘤的微血管生成,具有抗血管生成的作用。     

Pharmacological studies on a plant lectin,Aloctin A. I. Growth inhibition of mouse methylcholanthrene-induced fibrosarcoma (Meth A) in ascites form by Aloctin A

Summary A glycoprotein isolated fromAloe arborescens Mill markedly inhibited the growth of a syngeneic transplantable fibrosarcoma of mice, Meth A, in ascites form. There is evidence that the inhibition mechanism is host-mediated and not a direct toxic effect on the tumor cell.Acknowledgment. We thank Miss M. Hayama for her technical help.To whom all correspondence should be addressed.     

microRNA-451对人结肠癌细胞SW620裸鼠皮下种植瘤生长的抑制作用及机制探讨

目的 探讨microRNA-451(miR-451)对人结肠癌细胞系SW620裸鼠皮下种植瘤生长的影响,并探讨其可能机制.方法 18只裸鼠随机分为3组,实验组(SW-620-451组)、阴性对照组(SW-620-NC)、空白对照组(SW-620组),每组6只,分别皮下接种转染miRNA-451 agomir的SW620细胞、转染了阴性片段agomir Negative Control(NC)的SW620细胞和不经处理的结肠癌SW620细胞,并每周两次于瘤体内分别注射miRNA-451 agomir、miRNA-451 agomir NC片段及生理盐水.比较各组裸鼠皮下形成瘤体的大小并计算抑瘤率,接种四周后处死裸鼠取组织,用免疫组化法和Western-blot法定性定量分析和比较肿瘤相关基因c-myc的表达.结果 各组裸鼠皮下接种肿瘤细胞6天后均有瘤体形成,成瘤率100％,实验组(SW-620-451组)瘤体生长速度明显低于其他两组(p＜0.05);时间终点为第30天时,实验组(SW-620-451组)裸鼠皮下种植瘤的体积为(0.95±0.13)cm3,阴性对照组(SW-620-NC组)为(2.25±0.50) cm3,空白对照组(SW-620组)为(2.46±0.59)cm3;实验组(SW-620-451组)瘤体体积显著小于其他两组体积(p＜0.05);实验组(SW-620-451组)瘤体质量为(1.15±0.13)g,明显低于SW-620-NC组(2.59±0.46)g及SW-620组(2.76±0.44)g(p ＜0.05).实验组种植瘤中c-myc的表达量较另外两组下降(p＜0.05).结论 转染miR-451后可以抑制结肠癌细胞SW620裸鼠皮下移植瘤的生长,其机制可能与下调c-myc表达有关.     

The effect of dietary amino acids on the growth of tumors

Summary In C3H mice, a direct dose response relationship between tumor growth and dietary amino acid is seen for fibrosarcoma and mammary carcinoma, extending over a range the lower limit of which is defined by the minimum amino acid requirements, and the upper limit by the amino acid level found in most stock diets.Supported by Medical Research Council of Canada.     

Inhibition of transplanted mouse tumors by heterologous transfer RNA

Summary Injections of yeast tRNA to C57BL mice decreased takes and inhibited growth of syngeneic transplanted tumors. Mice remaining free of tumors as result of this treatment failed to develop tumors after challenge with 5×10⁴ cells of the same tumor.This work was supported in part by a grant from the Stanley Johnson Foundation, Berne, Switzerland.     

The effect of photodynamic therapy on tumor angiogenesis

Photodynamic therapy (PDT), the activation of a photosensitive drug in tumor tissue with light of specific wavelength, has been used effectively to treat certain solid tumors. Though therapeutic responses are encouraging, PDT-mediated oxidative stress can act as an angiogenic switch that ultimately leads to neovascularization and tumor recurrence. This article explores the effect of PDT on angiogenesis in different tumor models. Overexpression of proangiogenic vascular endothelial growth factor, cyclooxygenase-2 and matrix metalloproteases has often been reported post-illumination. Recent clinical studies have demonstrated that inhibiting angiogenesis after chemotherapy and radiotherapy is an attractive and valuable approach to cancer treatment. In this review, we report the effective therapeutic strategy of combining angiogenesis inhibitors with PDT to control and treat tumors.     

Effect of vitamin A on tumor development in burned, unburned, and glucocorticoid-treated mice inoculated with an oncogenic virus.

High doses of vitamin A decreased the severity of tumor development in mice inoculated with a murine sarcoma virus; the same doses of vitamin A had no effect on the increased tumorigenesis seen in animals severely stressed with thermal injury or the increased tumorigenesis induced by exogenous glucocorticoid administration.     

Effects of angiotensin II and of an angiotensin II receptor antagonist on simian virus 40-induced tumor growth in vivo

The effects of angiotensin II and of the competitive angiotensin II receptor antagonist saralasin on in vivo tumor growth were investigated in hamsters. Angiotensin II strongly inhibited tumor growth while saralasin stimulated it, though the high dose used had partial agonistic angiotensin II-like actions. Lower doses of saralasin were without significant effect on tumor weights.     

Failure of somatostatin to influence experimental tumor cell growth in vivo and in vitro

The influence of somatostatin on tumor cell growth was studied in vivo in mice (sarcoma 180 ascites tumor and Lewis lung tumor) and in vitro on nontransformed and polyoma-transformed cell lines. 4 or 20 micrograms/100 g of cyclic somatostatin and 4 micrograms/100 g of linear protamin Zn-bound somatostatin were injected s.c. twice daily in the in vivo study. Cyclic somatostatin (1, 4 or 10 micrograms/ml) was added twice daily to the cell cultures. Somatostatin administration influenced neither the survival of animals nor the growth rate of cultured cell lines.     

Zur Frage der genetischen Änderung eines Ascites-Hepatoms der Ratte durch Heterotransplantation auf chinesische Hamster

Summary Heterotransplantation of the rat hepatoma of Zajdela into golden hamsters, mice and Chinese hamsters has induced virtually no change in the neoplasm. The host tissues have shown, however, a 1% increase in their own mitoses, which is attributed to growth stimulation by the tumor.     

Effect of cyclophosphamide on development of reticulum cell sarcoma in SJL/J mice

Summary Studies to determine the effect of cyclophosphamide (CY) on the development of reticulum cell sarcoma (RCS) in SJL/J mice indicated a dependence on the duration of the test period. Age also appeared a factor of importance. Thus, a comparison of tumor incidences at 52 weeks of age showed maximal inhibition when CY was administered at 40 weeks, minimal inhibition when the drug was given at 30 weeks, and intermediate inhibition when treatment was initiated at 10 and 20 weeks. Consistent with these findings, long-term treatment of 40-week-old SJL/J mice with low doses of CY resulted in an increase in the mean survival time and in a reduction in the incidence of RCS. This work was supported in part by a University College Faculty Research Grant.     

Inhibition of tumor-induced angiogenesis and of tumor growth by activated lymphocytes

Summary Inhibition in angiogenesis (neo-vascularization) and of growth of a tumor piece graft in the anterior chamber of the eye of mice have been observed in the presence of activated syngeneic lymphocytes.Acknowledgment. The authors are thankful to ICMR, New Delhi, for financial assistance and to Mr N.C. Ghosh for illustration.     

甘氨双唑钠对鼻咽癌移植瘤的时辰放射增敏作用

目的 观察甘氨双唑钠（CMNa）联合时辰放疗对鼻咽癌祼鼠移植瘤的时辰放射增敏作用,并探讨其作用机制.方法 将荷瘤裸鼠随机分为3组：放疗组、放疗＋CMNa组、空白对照组,每组分3HALO（光照后小时,hours after light onset）、9HALO、15HALO、21HALO四个时辰进行相应处理.测定肿瘤再生长延长时间（regrowth delay time,TGD）,绘制生长曲线.用免疫组化法检测各组肿瘤标本中HIF-1α、γ-H2AX和凋亡蛋白的表达.结果 通过对各组TGD的比较.以放疗＋CMNa组对肿瘤的抑制效果最好.在该组中,TGD：15HALO＞21HALO＞9HALO＞3HALO,15HALO与3HALO的TGD比较有统计学意义 15HALO与3HALO的HIF-1α、γ-H2AX及凋亡蛋白的表达水平比较有统计学意义.结论 甘氨双唑钠联合时辰放疗对鼻咽癌裸鼠移植瘤有明显的时辰放射增敏作用,以15HALO放疗＋CMNa组对肿瘤的抑制效果最佳.其机制可能与HIF-1α的表达.DNA双链损伤,凋亡有关.     

全新结构抗肿瘤药物TNBG对裸鼠移植瘤生长抑制作用及药物毒副作用初步评价

目的观察TNBG对人肝癌细胞株QGY-7701裸鼠移植瘤生长抑制情况,初步评估药物的毒副作用。方法采用裸鼠复制人肝癌移植瘤模型。实验分对照组和给药组,腹腔注射给药,持续5周。治疗期间定期测量肿瘤大小,观察裸鼠生存状况。实验结束时处死裸鼠,测量肿瘤体积计算抑瘤率;眼眶取血,分离血清检测血脂、肝、肾功能;摘取裸鼠肿瘤及主要脏器组织作苏丹Ⅲ染色观察脂质沉积情况。结果TNBG对移植瘤的抑瘤率为60．1％;各实验组裸鼠血脂、肝、肾功检测与对照组比无显著性差异（P〉0．05）;苏丹Ⅲ染色显示给药组裸鼠主要脏器组织内无脂质沉积,而肿瘤组织中可见大量脂质沉积。结论TNBG对人肝癌细胞裸鼠移植瘤有较明显的抑制作用,毒副作用小,抗肿瘤作用具有选择性。     

CD24 controls Src/STAT3 activity in human tumors

CD24 is a glycosyl-phosphatidylinositol-anchored membrane protein that is frequently over-expressed in a variety of human carcinomas and is correlated with poor prognosis. In cancer cell lines, changes of CD24 expression can alter several cellular properties in vitro and tumor growth in vivo. However, little is known about how CD24 mediates these effects. Here we have analyzed the functional consequences of CD24 knock-down or over-expression in human cancer cell lines. Depletion of CD24 reduced cell proliferation and adhesion, enhanced apoptosis, and regulated the expression of various genes some of which were identified as STAT3 target genes. Loss of CD24 reduced STAT3 and FAK phosphorylation. Diminished STAT3 activity was confirmed by specific reporter assays. We found that reduced STAT3 activity after CD24 knock-down was accompanied by altered Src phosphorylation. Silencing of Src, similar to CD24, targeted the expression of prototype STAT3-regulated genes. Likewise, the over-expression of CD24 augmented Src-Y416 phosphorylation, the recruitment of Src into lipid rafts and the expression of STAT3-dependent target genes. An antibody to CD24 was effective in reducing tumor growth of A549 lung cancer and BxPC3 pancreatic cancer xenografts in mice. Antibody treatment affected the level of Src-phosphorylation in the tumor and altered the expression of STAT3 target genes. Our results provide evidence that CD24 regulates STAT3 and FAK activity and suggest an important role of Src in this process. Finally, the targeting of CD24 by antibodies could represent a novel route for tumor therapy.     

Ultrastructural study of somatotroph cells from mice bearing a fast growing transplanted hepatoma, in different periods of the tumor development.

The presence of a transplanted, fast-growing hepatoma (SS1-K) produces conspicuous ultrastructural changes in pituitary STH cells of C3H-S male mice. These changes are suggestive of an increased secretion of growth hormone only during the first stages of the tumor development. The hepatoma influence does not seem to be clearly related to the illumination regimen or time of killing.     

Role of plasminogen activator-plasmin system in tumor angiogenesis

New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and, conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand, genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.     

Inhibition of Ehrlich ascites carcinoma (EAC) growth by carbonyl iron

Summary Treatment of Ehrlich ascites carcinoma (EAC) cells with carbonyl iron (20 mg/ml) produces a significant decrease in growth rate of tumor inoculum both in Swiss and in C57BL/6 mice. Possible interaction of the carbonyl iron or Fe⁺⁺⁺ions with cell surface is suggested.Supported by a grant from the Consiglio Nazionale delle Ricerche.Acknowledgments. The authors are grateful to Dr M. M. Clynes (University College, Dublin, Ireland) for his helpful discussion.