Geometric Resistance and Microvascular Network Architecture of Human Colorectal Carcinoma

Objective : To measure the geometric resistance to blood flow in human colorectal carcinoma. Although tumor blood flow is of central importance in both the detection and the treatment of cancer, the determinants of blood flow through the neoplastic circulation are poorly understood. Methods : Human colorectal carcinomas (tissue weight = 272 g ± 43 g (SD), n = 6) were perfused ex vivo with a buffered physiological salt solution of known viscosity at flow rates ranging from 2.5 to 40 ml/min and perfusion pressures from 8 to 100 mm Hg. The geometric resistance was determined from the slope of the pressure-flow curve. For examination of the principal determinant of geometric resistance, the vascular architecture, one of the tumors was perfused with Batson's No. 17 polymer and macerated in KOH to produce a positive vascular cast that was used for measurement of vascular branching patterns and dimensions. Results : The pressure-flow relationship was linear at perfusion pressures above 40 mm Hg, and the geometric resistance, z₀, was constant at approximately 6.5 ± 10⁹g/cm³. Below 40 mm Hg, z₀ increased rapidly. The architecture of the arteriolar and capillary networks of human colorectal carcinoma is similar to those of experimental rodent tumors. Capillaries in planar and nonplanar mesh-works had mean segment diameters of 11 ± 2 and 9.6 ± 2 μm, lengths of 46 ± 24 and 107 ± 40 μm, and intercapillary distances of 46 ± 13 and 74 ± 24 μm, respectively. Conclusions : The geometric flow resistance in neoplastic tissue is 1–2 orders of magnitude higher than that observed in normal tissues. A decrease in functional vascular cross-sectional area may explain the additional increase in resistance at small perfusion pressures. The observed flow resistance may be due to the specialized arteriolar and capillary network architecture, pressures exerted by proliferating cancer cells, and/or coupling between vascular and extravascular flow. These observations demonstrate that tumor vascularity alone may not be indicative of flow resistance or tumor susceptibility to blood-borne therapeutic agents.     

SIX2在骨肉瘤组织中表达及其对细胞血管生成与阿霉素耐药逆转的影响

探究SIX2在骨肉瘤组织中表达及其对细胞血管生成与阿霉素耐药逆转的影响。方法 收集2019年3月—2021年12月我院行骨肉瘤手术切除的105例患者的组织标本,免疫组化检测骨肉瘤组织中SIX2表达和微血管密度（MVD）计数;检测骨肉瘤组织中SIX2 mRNA表达水平。将人骨肉瘤细胞系MG-63分为MG-63组、si-NC A组、si-SIX2 A组,将通过阿霉素耐药得到的骨肉瘤阿霉素耐药细胞株MG-63/R分为MG-63/R组、si-NC B组和si-SIX2 B组。分别用MTT法、克隆实验、流式细胞术及Transwell法检测细胞耐药性、细胞增殖、细胞凋亡和细胞侵袭。结果 在骨肉瘤组织中,SIX2阳性表达会随着MVD值升高而增加（P＜0.05）。骨肉瘤组织中SIX2阳性表达与TNM分期、软组织浸润和淋巴结远处转移相关（P＞0.05）。与MG-63组相比,si-SIX A组细胞的血管形成能力明显降低（P＜0.05）;与MG-63/R组相比,si-SIX2 B组细胞IC50、细胞克隆数和细胞侵袭能力均显著降低,细胞凋亡能力明显增加,细胞耐药指数逆转倍数为2.51倍（P＜0.05）。结论 SIX2在骨肉瘤组织中呈高表达,且随着SIX2表达的升高肿瘤血管生成能力也增加;抑制SIX2表达可有效抑制骨肉瘤组织的生成,逆转骨肉瘤细胞阿霉素耐药     

Prognostic factors in laryngeal carcinoma: the role of apoptosis,p53, proliferation (Ki-67) and angiogenesis

Even though the roles of different known or suggested prognostic factors in laryngeal cancer have been studied in detail, clinical stage at time of diagnosis and anatomic subsite of the tumour remain the only practical predictors of clinical outcome and offer the only guidelines in the planning of treatment. In this study, the relative roles of known demographic and clinical prognostic factors, in addition to four histopathological factors, were evaluated in a sample of 100 laryngeal carcinoma patients with multivariate analysis using the Cox regression model. In addition to advanced stage (stage III-IV) (relative hazard of death (HR) 8.9, p=0.01) and supraglottic disease (HR 5.6, p=0.02), high apoptotic index (HR 11.1, p=0.05) was significantly associated with poor survival. Cell proliferation, p53 and angiogenesis did not significantly affect the prognosis. In the future, high degree of apoptosis could be used to identify patients with poor prognosis in laryngeal cancer.     

Vascular endothelial growth factor overproduced by tumour cells acts predominantly as a potent angiogenic factor contributing to malignant progression

To elucidate the role of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, in tumour angiogenesis and malignant progression, an expression vector harboring human VEGF cDNA was stably transfected into three human cancer cell lines with poor VEGF productivity. Though their in vitro growth rate and intrinsic productivity of another angiogenic factor, basic fibroblast growth factor (bFGF), were not changed by transfection, those clones with higher VEGF production were endowed with tumorigenic and angiogenic potentials as follows: firstly, nontumorigenic, lung carcinoma QG90 cells having lower bFGF productivity acquired tumorigenicity as well as significant in vivo angiogenesis-inducing ability, secondly, tumorigenic colorectal carcinoma RPMI4788 cells having higher potency for bFGF production could form more vascularized solid tumour with faster growth rate and thirdly, oestrogen-dependent breast carcinoma MCF-7 cells, which did not produce detectable bFGF, acquired tumorigenicity even in the absence of oestrogen and the solid tumour growth rate was remarkably enhanced, accompanied with increased vascularization, in the presence of oestrogen. These results suggest that tumour progression closely depends on angiogenesis, and VEGF significantly contributes to malignant progression of a variety of tumour cells through its potent angiogenic activity, independent on the bFGF productivity of tumour cells.     

Vasculogenic mimicry has no prognostic significance in pT3 and pT4 cutaneous melanoma

The concept of vasculogenic mimicry has been introduced to define periodic acid-Schiff (PAS)-positive channels and loops lined by tumor cells, instead of endothelium, able to contribute to microcirculation in uveal melanomas. Previous studies have shown that the PAS-positive patterns are associated with a poor prognosis in uveal melanoma. The aim of the current study was to investigate whether vasculogenic mimicry has a prognostic impact in pT3 and pT4 cutaneous melanoma. Fifteen patients with pT3 and pT4 cutaneous melanoma who did not experience progression after 10 years of follow-up and 30 matched controls who underwent progression were selected. Tumor sections were stained with PAS reaction, omitting the nuclear counterstaining. For immunohistochemistry, sections were stained with CD31, CD105 (endoglin), and laminin. Differences in the distribution of the PAS-positive patterns and a series of clinicopathological variables were evaluated by the Pearson chi(2) and Mann-Whitney U tests. We observed PAS-positive linear sheets, arcs, elliptical loops, and networks encircling roundish to oval aggregates of melanoma cells. The overall distribution of the PAS-positive patterns did not match with the blood microvessels' architecture as detected by immunohistochemical analysis. No statistically significant differences in the distribution of PAS-positive patterns were found between cases and controls. The presence of a parallel pattern correlated significantly with thickness (P = 0.04), whereas an inverse correlation was found with vessel area (P = 0.05). In conclusion, our results suggest that there is a mismatch between vasculogenic mimicry and tumor angiogenesis and do not support any prognostic role of vasculogenic mimicry in thick cutaneous melanoma.     

右旋柠烯乳剂对人胃癌移植瘤生长和转移的抑制作用

目的　研究并探讨右旋柠烯乳剂 (D limonene)对人胃癌生长和转移的抑制作用及其机制。　方法　采用人胃癌BGC 82 3细胞株经反复传代成实体瘤的完整组织块 ,建立人胃癌裸小鼠原位移植瘤模型。将 4 0只荷瘤裸小鼠随机分成 4组 ,移植后第 5d开始分别用生理盐水灌胃、5 氟尿嘧啶 (5 FU)腹腔注射、D limonene灌胃、D limonene灌胃 +5 FU腹腔注射共 7周。第 8周处死动物 ,测量原位肿瘤瘤重并计算抑瘤率 ,检测肿瘤细胞凋亡指数 (AI)、肿瘤微血管密度 (MVD)及免疫组织化学测定肿瘤组织血管内皮生长因子 (VEGF)的表达变化 ,光镜与电镜观察组织细胞超微结构变化 ;观察荷瘤鼠腹膜、肝、其他脏器肿瘤转移及腹水情况。　结果　D limonene组、联用组分别与对照组相比 ,胃癌的原位肿瘤瘤重与抑瘤率、AI、MVD、VEGF下调 ,差异有显著性 (P <0 0 5 )。腹膜、肝转移受到明显抑制 (P <0 0 5 )。　结论　D limonene通过抑制肿瘤微血管形成 ,诱导胃癌细胞凋亡 ,抑制了体内胃癌的生长和转移。     

Social isolation stress augments angiogenesis induced by colon 26-L5 carcinoma cells in mice

We have previously shown that tumor necrosis factor-α (TNF-α), which is an important angiogenesis-related factor, was over-secreted in male BALB/c mice under social isolation stress as compared with the control, and closely associated with a remarkable elevation of tumor invasion and metastasis of colon 26-L5 carcinoma cells. In the present study, we explored the effect of isolation stress on the angiogenesis caused by colon 26-L5 carcinoma cells in vivo and in vitro. Social isolation lead to the enhancement of tumor growth after intrahepatic implantation with a fragment of colon 26-L5 tumor. Angiogenic response (number of vessels oriented towards tumor mass) and tumor growth (size) were significantly increased in the socially isolated mouse relative to that in the group-housed mice. Furthermore, higher protein level of hepatic TNF-α was found in the stressed mice than that in the control. Expression of mRNA for vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) were also elevated in the tumor regions and liver tissues of the stressed mice in comparison with that in group-housed mice. On the other hand, hepatic sinusoidal endothelial (HSE) cells treated with TNF-α exhibited a marked promotion of the migration, invasion, expression of mRNA for matrix metalloproteinase (MMP)-9, and tube-like formation, but no cytotoxicity against the cells in vitro. The above data suggest that the social isolation stress augmented the tumor-induced angiogenesis probably by up-regulating the angiogenesis-related factors, including TNF-α, VEGF and HGF, and consequently mediating the functions of endothelial cells such as migration, invasion, and tube-like formation.     

Robo家族蛋白在神经元轴突发育和肿瘤血管生成中的作用

Robo家族（Roundabout family）是与发育有关的保守跨膜蛋白家族，主要表达于神经系统并在神经元轴突发育中发挥重要作用。近期，人们研究发现Robo家族的一个新成员Robo4(又称magic roundabout,MRB)特异表达于血管生成活跃的内皮细胞表面，并参与调控内皮细胞迁移。成年人正常组织中不表达MRB，而肿瘤组织相对特异性高表达，MRB有望成为抑制血管生成治疗肿瘤的新靶点。     

小胶质细胞极化介导炎症反应在脊髓损伤中的作用

背景:小胶质细胞极化参与脊髓损伤后的炎症反应,并在其中发挥关键作用。相关研究表明,有效诱导小胶质细胞从M1促炎表型向M2抗炎表型极化,可以减轻脊髓损伤后的炎症反应,促进组织的修复再生和神经功能的恢复。目的:文章对小胶质细胞的功能和极化、小胶质细胞极化对脊髓损伤的影响及其潜在调控策略以及脊髓损伤后炎症反应进行综述。方法:检索PubMed、Web of Science和中国知网数据库,英文检索词为“microglia,polarization,spinal cord injury,inflammation”,中文检索词为“小胶质细胞、极化、脊髓损伤、炎症”,按纳入和排除标准共纳入80篇文献进行总结。结果与结论:①由小胶质细胞介导的稳定而持续的炎症反应,对脊髓损伤的预后至关重要。②在生理条件下,小胶质细胞处于M0静止表型,但在脊髓损伤后,小胶质细胞活化,进而极化成M1促炎表型,导致神经组织修复能力降低和出现持续性神经炎症。③在脊髓损伤的炎症反应过程中,调控小胶质细胞向M2表型极化或至少向M2表型倾斜,有利于抑制氧化应激反应、调节突触重塑、促进轴突再生和血管生成,是一种有效的调控策略。④截止到目前的研究表明,间充质干细胞、外泌体、临床药物、天然产物、miRNAs和靶点分子可调控小胶质细胞在M1和M2表型之间的转换,这为脊髓损伤后神经组织的修复提供了一种新的思路,未来需进一步研究小胶质细胞在脊髓损伤过程中调控极化的详细机制。     

Evidence for the causal role of endogenous interferon-alpha/beta in the regulation of angiogenesis,tumorigenicity, and metastasis of cutaneous neoplasms

Primary tumor growth and metastasis depend on angiogenesis, which is determined by the balance between proangiogenic and antiangiogenic molecules. Interferon (IFN)-α and -β inhibit angiogenesis through downregulation of interleukin-8, matrix metalloproteinase-9, and basic fibroblast growth factor. To provide evidence for the causal role of IFN-α/β in the induction of neoplasms, their angiogenesis, and hence, progressive growth, we carried out experiments using 129S6 IFN-α/β receptor −/− mice back-crossed to BALB/c nude mice. Subcutaneous angiogenesis was determined following implantation of gelfoam sponges containing 0.4% agarose and several proangiogenic molecules. Tumorigenicity and production of lung metastasis were determined subsequent to subcutaneous and intravenous injections, respectively, of highly metastatic A375SM human melanoma cells. Carcinogenesis was induced by chronic exposure of mice to UVB radiation (5 kJ/m², 3 times/week). Angiogenesis, tumorigenicity, and production of metastasis, as well as development of autochthonous skin tumors, were all accelerated in IFN-α/β receptor −/− mice as compared to control mice. Collectively, the data show that inability to respond to endogenous IFN-α/β (through a mutation in the IFN-α/β receptor) leads to increased susceptibility to carcinogenesis, enhanced angiogenesis, tumorigenicity, and metastasis. This revised version was published online in July 2006 with corrections to the Cover Date.