The relationship between the tumor physiologic microenvironment and angiogenesis

This article examines the pathophysiology of tumors, with an emphasis on how these features influence angiogenesis in tumors.     

Oxidative stress in tumor microenvironment——Its role in angiogenesis

The tumor angiogenesis process is believed to be dependent on an "angiogenic switch" formed by a cascade of biologic events as a consequence of the "cross-talk" between tumor cells and several components of local microenvironment including endothelial cells, macrophages, mast cells and stromal components. Oxidative stress represents an important stimulus that widely contributes to this angiogenic switch, which is particularly relevant in lungs, where oxidative stress is originated from different sources including the incomplete reduction of oxygen during respiration, exposure to hypoxia/reoxygenation, stimulated resident or chemoattracted immune cells to lung tissues, as well as by a variety of chemicals compounds. In the present review we highlight the role of oxidative stress in tumor angiogenesis as a key signal linked to other relevant actors in this complex process.     

Influence of the tumor microenvironment on angiogenesis

It is becoming increasingly recognized that the host microenvironment is essential for regulating tumor cell behavior. The cellular stromal compartment can modulate angiogenesis either directly through enhanced secretion of pro-angiogenic factors or reduced secretion of antiangiogenic factors, or indirectly by modulating the surrounding extracellular matrix. Control of angiogenesis represents a critical step in cancer progression and is a potential therapeutic target. This article focuses on the role of the tumor microenvironment in the control of angiogenesis and how dissection of the molecular interactions may enhance prognostic and predictive power and facilitate therapeutic targeting.     

肿瘤微环境在肿瘤淋巴管生成中的作用

恶性肿瘤淋巴结转移是一个复杂的病理过程,与肿瘤淋巴管生成密切相关。肿瘤生长到一定程度,分泌某些淋巴管生长因子,在肿瘤周围或内部形成新生淋巴管,肿瘤细胞侵入管腔并通过淋巴液顺次流入各站淋巴结,逐渐形成淋巴结转移病灶。正常细胞处于一个相对稳定的内环境,按正常的程序进行着增殖、分化、凋亡以及相关因子的分泌和表达,而肿瘤发生、发展则不断打破这一平衡,逐渐形成一个适于自己生长的组织外环境,即肿瘤微环境。而肿瘤微环境中的众多促淋巴管生成因子、炎性条件、组织缺氧、酸性微环境以及间质高压形成等病理生理特性能促进肿瘤淋巴管生成,进而促进肿瘤淋巴结转移病灶的形成。      

The tumor microenvironment and its role in promoting tumor growth

The tumor microenvironment is created by the tumor and dominated by tumor-induced interactions. Although various immune effector cells are recruited to the tumor site, their anti-tumor functions are downregulated, largely in response to tumor-derived signals. Infiltrates of inflammatory cells present in human tumors are chronic in nature and are enriched in regulatory T cells (T(reg)) as well as myeloid suppressor cells (MSC). Immune cells in the tumor microenvironment not only fail to exercise antitumor effector functions, but they are co-opted to promote tumor growth. Sustained activation of the NF-kappaB pathway in the tumor milieu represents one mechanism that appears to favor tumor survival and drive abortive activation of immune cells. The result is tumor escape from the host immune system. Tumor escape is accomplished through the activation of one or several molecular mechanisms that lead to inhibition of immune cell functions or to apoptosis of anti-tumor effector cells. The ability to block tumor escape depends on a better understanding of cellular and molecular pathways operating in the tumor microenvironment. Novel therapeutic strategies that emerge are designed to change the pro-tumor microenvironment to one favoring acute responses and potent anti-tumor activity.     

The role of autocrine motility factor in tumor and tumor microenvironment

Autocrine motility factor (AMF) is a tumor-secreted cytokine and is abundant at tumor sites, where it may affect the process of tumor growth and metastasis. AMF is a multifunctional protein capable of affecting cell migration, invasion, proliferation, and survival, and possesses phosphoglucose isomerase activity and can catalyze the step in glycolysis and gluconeogenesis. Here, we review the role of AMF and tumor environment on malignant processes. The outcome of metastasis depends on multiple interactions between tumor cells and homeostatic mechanisms, therefore elucidation of the tumor/host interactions in the tumor microenvironment is essential in the development of new prevention and treatment strategies. Such knowledge might provide clues to develop new future therapeutic approaches for human cancers.     

The role of integrins in tumor angiogenesis

Integrins are cell adhesion molecules that play an important role in the regulation of angiogenesis. In this overview, the vascular integrins and their mechanisms of action are outlined. Integrins have been evaluated in preclinical and clinical studies for the treatment of cancer and as diagnostic markers of angiogenesis. Furthermore, integrins are the basis for targeted therapy for solid tumors and novel imaging techniques to assess the angiogenic response of tumors.     

The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis

Although a considerable amount of effort has been placed on discovering the etiologies of cancer, the majority of the basic cancer research existing today has focused on understanding the molecular mechanism of tumor formation and metastasis. Metastatic spread of tumors continues to be a major obstacle to successful treatment of malignant tumors. Approximately 30% of those patients diagnosed with a solid tumor have a clinically detectable metastasis and for the remaining 70%, metastases are continually being formed throughout the life of the tumor. Even after the tumor is excised, the threat of death is attributable to the metastasis that may occur through the remaining tumor cells. In addition, treating the metastasis often proves futile since metastasis often vary in size, composition, and anatomical location. New treatments blocking the formation of metastasis will provide greater chances of survival for cancer patients. One family of enzymes that has been shown over the years to play a role in tumor progression is the matrix metalloproteinase (MMP) family. The main function of MMPs, also known as matrixins, is degradation of the extracellular matrix physiologic function involving MMPs include wound healing, bone resorption and mammary involution. MMPs, however, also contribute to pathological conditions including rheumatoid arthritis, coronary artery disease, and cancer. Tumor cells are believed to utilize the matrix degrading capability of these enzymes to spread to distant sites. In addition, MMPs also are thought to promote the growth of these tumor cells once they have metastasized. This review will discuss the role of MMPs and their inhibitors in tumor invasion, angiogenesis and metastasis with special emphasis on the gelatinases, MMP-2 and MMP-9.     

The role of angiogenesis in tumor growth.

Experimental and clinical evidence is here assembled in support of the concept that the development of a solid tumor progresses from a prevascular phase to a vascular phase. The prevascular tumor does not induce angiogenesis, is limited in size, and rarely metastasizes. The vascularized tumor induces host microvessels to undergo angiogenesis, has the potential to rapidly expand its cell population, and has a propensity to metastasize. Thus, angiogenesis is necessary but not sufficient for tumor growth and metastasis. Neovascularization of a tumor requires that a critical number of its cells have switched to the angiogenic phenotype. The mechanisms by which tumor cells become angiogenic, subjects of current study, are reviewed here. At least two general categories are recognized: (i) angiogenic activity arises from the tumor cell itself in the form of the release of angiogenic molecules such as basic fibroblast growth factor; (ii) angiogenic activity arises from host cells recruited by the tumor (e.g. macrophages), or is mobilized from the extracellular matrix, or requires concomitant loss of physiological inhibition of endothelial cell proliferation. Accumulating evidence indicates that for most tumors, the switch to the angiogenic phenotype depends upon the outcome of a balance between angiogenic stimulators and angiogenic inhibitors, both of which may be produced by tumor cells and perhaps by certain host cells.     

The role of nuclear pore complex in tumor microenvironment and metastasis

One of the main reasons for cancer mortality is caused by the highly invasive behavior of cancer cells, which often due to aggressive metastasis. Metastasis is mediated by various growth factors and cytokines, operating through numerous signaling pathways. Remarkably, all these metastatic signaling pathways must enter the nucleus through a single gatekeeper, the nuclear pore complex (NPC). NPCs are the only gateway between the cytoplasm and the nucleus. NPCs are among the largest proteinaceous assemblies in the cell and are composed of multiple copies of around 30 different proteins called nucleoporins. Here, we review what is currently known about the NPC, and its role in the mechanisms of tumor progression. We will also explore potential strategies to target metastatic pathways by manipulating the karyopherins (importins/exportins) of nucleocytoplasmic traffic through NPCs.     

Breast cancer-induced angiogenesis: multiple mechanisms and the role of the microenvironment

Growth and progression of breast cancers are accompanied by increased neovascularization (angiogenesis). A variety of factors, including hypoxia and genetic changes in the tumor cells, contribute to increased production of angiogenic factors. Furthermore, cells within the activated tumor stroma also contribute to the increase in production of vascular endothelial growth factor and other angiogenic factors, including basic fibroblast growth factor and platelet-derived growth factor. The contribution of the microenvironment to tumor-induced angiogenesis is underscored by findings that breast tumors implanted into different tissue sites show marked differences in the extent and nature of the angiogenic response. These findings have important implications for designing anti-angiogenic therapies.     

铁代谢在肿瘤免疫微环境中的作用及其在肿瘤治疗中的应用

铁代谢的动态平衡是维持细胞代谢正常的基本条件,而肿瘤免疫微环境（TIME）的铁代谢在肿瘤发生发展中扮演着重要角色,具有针对肿瘤细胞和免疫细胞的双面性的特点,并且在原发性和转移性肿瘤以及各类免疫细胞的不同亚型中体现异质性。TIME中的巨噬细胞和中性粒细胞等免疫细胞铁代谢失调,以及T细胞和中性粒细胞等免疫细胞诱导的铁死亡均可调控肿瘤的发生发展。近年来免疫相关治疗迅速发展,以TIME铁代谢作为治疗靶标的铁螯合剂、铁相关纳米粒子、铁代谢联合放疗或免疫检查点阻断疗法等为肿瘤患者的治疗和预后提供了新思路,随着TIME铁代谢的研究不断深入,针对其代谢特点进行调控,将可以为肿瘤免疫治疗领域提供更多的治疗手段。     

Survivin与VEGF在结直肠肿瘤血管形成中的作用

目的探讨Survivin、血管内皮生长因子（VEGF）在结直肠肿瘤血管形成中的作用。方法对11例增生性息肉、23例低度异型增生腺瘤、20例高度异型增生腺瘤、29例腺瘤恶变组织和65例腺癌组织使用Survivin多克隆抗体、VEGF和CD34单克隆抗体、标准化的链霉菌抗生物素蛋白-过氧化物酶技术（SP法）对存档组织块切片进行免疫组化染色,并用MIRS-2000图像分析系统分析其阳性率及表达程度,并行微血管密度（MVD）计数。结果Survivin表达与VEGF表达及MVD密切相关,且呈明显正相关（r均为0．711,P〈0．01）。MVD与VEGF表达呈明显正相关（r=0．711,P〈0．01）。Survivin／VEGF双阳性组较阴性／阳性组及双阴性组MVD值显著增高（P均〈0．01）,同时对于Survivin／VEGF阳性／阴性组,其MVD值与双阳性组差异无统计学意义（P〉0．05）。结论Survivin与VEGF表达密切相关,二者协同作用促进结直肠肿瘤血管生成;VEGF可能是结直肠癌中Survivin再表达的原因之一。     

Survivin与VEGF在结直肠肿瘤血管形成中的作用

目的 探讨Survivin、血管内皮生长因子(VEGF)在结直肠肿瘤血管形成中的作用.方法 对11例增生性息肉、23例低度异型增生腺瘤、20例高度异型增牛腺瘤、29例腺瘤恶变组织和65例腺癌组织使用Survivin多克隆抗体、VEGF和CD34单克隆抗体、标准化的链霉菌抗生物素蛋白-过氧化物酶技术(SP法)对存档组织块切片进行免疫组化染色,并用MIRS-2000图像分析系统分析其阳性率及表达程度,并行微血管密度(MVD)计数.结果 Survivin表达与VEGF表达及MVD密切相关,且呈明显正相关(r均为0.711,P<0.01).MVD与VEGF表达呈明显正相关(r=0.711,P<0.01).Survivin/VEGF双阳性组较阴性/阳性组及双阴性组MVD值显著增高(P均<0.01),同时对于survivin/VEGF阳性/阴性组,其MVD值与双阳性组筹异无统计学意义(P0.05).结论 Survivin与VEGF表达密切相关,二者协同作用促进结直肠肿瘤血管生成;VEGF可能是结直肠癌中Survivin冉表达的原因之一.     

The tumor microenvironment

The concept of the tumor microenvironment, developed from Paget's "seed and soil" theory is made up of the cancer cells, the stromal tissue, and the extracellular matrix. In this mini-review, each of the components of this dynamic network will be examined. We will show that there are a multitude of complex interactions and a host of molecules involved in tumorogenesis and metastasis. We will further illustrate this notion with examples from the tumor microenvironment of breast cancer. Lastly, we conclude with thoughts about how this will influence the surgical field with examples of therapeutic agents already in use that target aspects of this microenvironment.     

The role of stromal myofibroblast and extracellular matrix in tumor angiogenesis

Tumor angiogenesis, the building of blood vessels in an expanding tumor mass, is an elegantly coordinated process that dictates tumor growth and progression. Stromal components of the tumor microenvironment, such as myofibroblasts and the extracellular matrix, collaborate with tumor cells in regulating development. Such myofibroblasts and the extracellular matrix have ever-expanding roles in the angiogenic process as well. This review summarizes how stromal myofibroblasts and the extracellular matrix can modulate tumor angiogenesis, highlighting recent findings.