New Approaches to the Treatment of Hepatic Malignancies Angiogenesis and Antiangiogenic Therapy of Colon Cancer Liver Metastasis

The fact that tumor growth and metastatic spread relies on angiogenesis has been widely proven and accepted. The understanding of cancer biology and metastasis formation has led to the development of new therapeutic approaches that target tumor biology. The survival and establishment of metastatic lesions depend on a shift in the normal balance of proangiogenic and antiangiogenic factors that favor angiogenesis. Colorectal cancer is one of the leading cancer deaths worldwide. Angiogenesis has been associated with colon cancer progression and metastatic spread, thereby significantly affecting patient survival. New experimental approaches that inhibit angiogenic processes have demonstrated promising antineoplastic effects on metastatic colorectal cancer and are partially being investigated in clinical trials. This review focuses on angiogenesis in colorectal cancer metastasis formation as a target for antiangiogenic therapy, describing the experience from experimental studies and current clinical trials.     

以肿瘤干细胞为靶点的肿瘤治疗新策略

肿瘤干细胞(cancer stem cells,CSCs)是存在于肿瘤组织中具有干细胞性质的细胞亚群,目前在脑肿瘤、乳腺癌、前列腺癌和结肠癌等实体瘤中均获得鉴定.CSCs具有自我更新的能力,被认为是肿瘤的起源.近年来,以CSCs为治疗靶点的研究已成为肿瘤治疗的新研究领域.     

The role of cancer stem cells in neoplasia of the lung: past,present and future

Through the identification and subsequent targeting of an exquisitely unique and phenotypically defined cancer stem-cell population exhibiting discrete therapeutic vulnerabilities (a potential source of tumor recurrence) better survival rates for these patients may be achieved. It is this impetus that is making the field of pulmonary stem cell biology a growing field in biomedicine. These efforts are leading to the steady identification of multi-potent, self-renewing and proliferative progenitor cell populations throughout the bronchopulmonary tree. These cells give rise to both transiently amplifying (TA) and terminally differentiated (TD) cells, which (like in many other organs) are crucial for tissue homeostasis. In leukemia, it has been shown that partially committed cells, which are normally responsible for tissue maintenance after trauma, may undergo transformation via mutations resulting in the selective expression of genes that accentuate and perpetuate these cells’ self-renewal capabilities. It is therefore perhaps legitimate to consider stem cells as protumorigenic. It is when these cells undergo genetic mutations which make them acquire the ability to metastasize, that cancer occurs, rendering the concept of ‘cancer stem cells’ a rather attractive one indeed.     

Selective and sensitive fluorescence imaging reveals microenvironment-dependent behavior of NO modulators in the endothelial system

Nitric oxide (NO) is a second messenger playing crucial roles in the signaling of a variety of cellular functions. Due to its pathophysiological significance, various NO modulators have been developed to explore NO pathways and some have been used as therapies. These modulators are often used directly to observe pharmacological effects in cell lines, but their actual effect on intracellular NO level is seldom analyzed. Herein, facilitated by a selective and sensitive fluorescence probe, we observed that some NO modulators displayed unexpected behaviors with both NO scavenger carboxy-PTIO and endothelial nitric oxide synthase (eNOS) inhibitor N(ω)-nitro-l-arginine methyl ester (l-NAME) failing to decrease intracellular free NO level in EA. hy926 cells while NO donor diethylamine-NONOate (DEA·NONOate) and eNOS activator calcimycin (A23187) failing to increase free NO level in human umbilical vein endothelial cell line (HUV-EC-C), although the reagents were confirmed to work normally in the primary human umbilical vein endothelial cells (primary HUVECs) and RAW 264.7 macrophage cells. Further research suggested that these unusual behaviors might be attributed to the cellular microenvironments including both the NO synthase (NOS) level and the endogenous glutathione (GSH) level. Genetically manipulating eNOS level in both cells restores the expected response, while decreasing GSH level restores the ability of DEA·NONOate to increase NO level in HUV-EC-C. These results reveal that the cellular microenvironment has a profound impact on pharmacological effect. Our study suggests GSH as a reservoir for NO in live cells and highlights the value of chemical probes as valuable tools to reveal microenvironment-dependent pharmacological effects.     

NFATc1 is Suppressed in Tumor Microenvironment of Hodgkin Lymphoma

Objective: The aims of this research are to evaluate the expression and distribution of NFATc1 in tumor microenvironment of Hodgkin lymphoma. Methods: Twenty-eight cases of Hodgkin lymphoma were selected. Clinicopathological data of age, gender, location and subtypes were obtained. Immunohistochemistry was performed to the all cases by using anti-CD163, anti-NFATc1 and anti-PD-L1 antibodies. All protein expression was calculated by using Image J software. Results: Nuclear expression of NFATc1 was not observed in Hodgkin cells neither in TAM nor in small lymphocytes surrounding Hodgkin cells in all the samples, this meant that NFATc1 showed negative nuclear expression in almost all these cells. Cytoplasmic expression of NFATc1 was observed in small lymphocytes surrounding tumor cells. While there were only few small lymphocytes which were located far from tumor cells showed nuclear expression of NFATc1. Meanwhile, 57.14% samples showed high density of TAMs CD163+, and 50% tumor cells as well as 50% TAMs exhibited positive PD-L1 expression. In addition, all macrophages did not have NFATc1 expression both in their nuclei and in their cytoplasm. Conclusion: NFATc1 was suppressed both in Hodgkin cells and inflammatory cells surrounding the tumor cells. This condition may contribute to progressivity and aggressiveness of the diseases. Therefore, certain mechanisms to reactivate functional NFATc1 in HL tumor microenvironment may be necessary; hence, the tumor cells are able to be eradicated by patient’s immune mechanisms.     

食管鳞癌肿瘤微环境相关研究进展

食管鳞癌是我国食管癌的主要类型，危害严重。近年来，许多研究发现，其发生、发展与所在的肿瘤微环境密切相关。食管鳞癌细胞所在的肿瘤微环境可通过调控免疫微环境、释放细胞因子、改变血管生成等多种途径促进食管鳞癌细胞生长、侵袭和转移，并造成免疫逃逸。本综述从白介素-6（interleukin-6，IL-6）、程序性死亡［蛋白］-1（programmed death-1，PD-1）/程序性死亡［蛋白］配体-1（programmed death ligand-1，PD-L1）、转化生长因子-β（transforming growth factor-β，TGF-β）、乏氧诱导因子-1（hypoxia inducible factor-1，HIF-1）及血管内皮细胞生长因子（vascular endothelial growth factor，VEGF）等影响食管鳞癌肿瘤微环境的重要通路方面，阐述肿瘤微环境与食管鳞癌预后的关系及相关机制，并介绍相关靶向治疗的研究进展，旨在为食管鳞癌的防治研究提供参考。     

肿瘤微环境与耐药的发生在恶性血液病中研究进展

肿瘤微环境与肿瘤细胞相互作用可以导致肿瘤细胞发生耐药,称为肿瘤微环境介导的细胞耐药(EM-DR)。EM-DR主要包括细胞黏附介导的耐药(CAM-DR)、可溶性因子介导的耐药(SM-DR)和其它途径诱导的耐药。SM-DR涉及大量的因子,这些因子主要通过促进恶性血细胞存活与增殖,抑制恶性血细胞凋亡导致细胞对药物不敏感。CAM-DR的研究主要通过肿瘤耐药细胞模型完成的,常见模型包括:球形模型、FN模型、间质模型。通过对模型研究发现肿瘤微环境可通过不同信号通路向细胞提供存活信号,从而导致耐药发生。另外肿瘤微环境还可调节耐药基因表达或局部的pH值诱导恶性血细胞发生耐药。本文就肿瘤微环境介导的恶性血液病细胞耐药的研究进展做一综述。     

Transplanted Abdominal Granulation Tissue Induced Bone Formation—An In Vivo Study in Sheep

Many wounds to both soft and hard tissues heal via the formation of a granulation tissue bed. This bed is supportive of neoangiogenesis and releases proangiogenic, migratory, and proliferative growth factors and cytokines. In this study granulation tissue was grown on an intraperitoneal implant (4 mm diameter, 20 mm length) in a sheep. After 2 weeks, this implant was removed and transplanted into a femoral bone defect (4 mm diameter, 20 mm length). The sheep were sacrificed after 3 months, and the implant site examined using micro-CT and histology. A bone plaque formed adjacent to the implant, only in the presence of the peritoneal granulation tissue. This suggests that the formation of granulation tissue is a relatively conserved response at various locations in the body and its transplantation from one location to another can be used to induce tissue healing. This technique may prove useful as a method of improving physiological response to biomaterials.     

Association of an Impaired Bone Marrow Microenvironment with Secondary Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation

Poor graft function (PGF) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Whether abnormalities of the bone marrow (BM) microenvironment are involved in the pathogenesis of PGF is unclear. In the present prospective nested case-control study, 19 patients with secondary PGF, 38 matched patients with good graft function (GGF) after allo-HSCT, and 15 healthy donors (HDs) were enrolled. The cellular elements of the BM microenvironment, including endosteal cells, perivascular cells, and vascular cells, were analyzed by flow cytometry as well as hematoxylin and eosin and immunohistochemical staining in situ. The median time to occurrence of secondary PGF was 90 days post-transplantation (range, 58 to 264 days). The patients with PGF showed markedly hypocellular marrow (10% versus 45% versus 45%; P < .0001) with scattered hematopoietic cells and significantly lower CD34⁺ cells (0.07% versus 0.26% versus 0.26%; P < .0001), endosteal cells (4 per high-power field [hpf] versus 16 per hpf versus 20 per hpf; P < .001), perivascular cells (0.008% versus 0.10% versus 0.12%; P < .0001), and endothelial progenitor cells (0.008% versus 0.16% versus 0.18%; P < .0001) compared with GGF allo-HSCT recipients and HDs, respectively. Multivariate analyses revealed that endothelial progenitor cells (odds ratio, 150.72; P = .001) and the underlying disease (odds ratio, 18.52; P = .007) were independent risk factors for secondary PGF. Our results suggest that the impaired BM microenvironment may contribute to the occurrence of secondary PGF post-HSCT.