肿瘤相关巨噬细胞与肿瘤关系的研究进展

肿瘤相关巨噬细胞（ Tumor associate macrophages ,TAMs）是肿瘤的炎症微环境与肿瘤细胞间的重要信使。它是从血液中的单核细胞演变而来,主要通过集落刺激因子（ Colony -stimulating factor , CSF）趋化至肿瘤组织中。本文简述了TAMs通过影响血管生成和淋巴管生成,抑制免疫,调节基质,与干细胞相互作用等方面促进肿瘤的进展。分析表明靶向于TAMs的治疗策略是未来治疗肿瘤的一个新方向。     

The controversial role of placental growth factor in tumor growth

The significance of placental growth factor (PlGF) in tumor growth is still a matter of debate. Depending on the model, PlGF overexpression has been shown to result in tumor growth promotion or inhibition. This review article summarizes the most relevant literature data concerning this still unsolved important question.     

Distinct role of macrophages in different tumor microenvironments

Macrophages are prominent in the stromal compartment of virtually all types of malignancy. These highly versatile cells respond to the presence of stimuli in different parts of tumors with the release of a distinct repertoire of growth factors, cytokines, chemokines, and enzymes that regulate tumor growth, angiogenesis, invasion, and/or metastasis. The distinct microenvironments where tumor-associated macrophages (TAM) act include areas of invasion where TAMs promote cancer cell motility, stromal and perivascular areas where TAMs promote metastasis, and avascular and perinecrotic areas where hypoxic TAMs stimulate angiogenesis. This review will discuss the evidence for differential regulation of TAMs in these microenvironments and provide an overview of current attempts to target or use TAMs for therapeutic purposes.     

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 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.     

肿瘤相关巨噬细胞的极化与肿瘤的发展

肿瘤相关巨噬细胞（TAM）在肿瘤微环境中扮演重要角色,它包含了两种可以相互极化的亚型:M1型(经典活化巨噬细胞)和M2型（替代活化巨噬细胞）。M1型TAM发挥着抑制肿瘤生长的作用,而M2型TAM对肿瘤的发生发展起促进支持作用。在特定的肿瘤微环境中,M2型TAM占据主导地位,促进肿瘤的发展。基于肿瘤相关巨噬细胞两种亚型的功能特点,如何诱导M2型向M1型极化是目前的研究热点,也将是肿瘤治疗的一个重要靶点。     

The role of macrophages in asbestos-induced carcinogenesis

Data available on the pathways of asbestos (fibrous) carcinogenesis still leaves much to be desired. Asbestos is regarded as a non-genotoxic substance by most researchers. There is insufficient evidence on the interaction of fibres, target-cells and macrophages. Macrophages secreted proteins (ca. 450 kD) to inhibit proliferation of intact mesothelium and cytoxine (3-5 kD) which stimulated the cellular sensitivity of intact mesothelium and mesotheliomas to the toxic influence of asbestos. It was suggested that the effect was due to the triggering of intrinsic causation of cell death. Like any other fibres, carcinogenic effect of asbestos could be accounted for by such significant factor as active oxygen radicals. When exposed to asbestos, both intact mesothelial and mesothelioma cells and macrophages synthesized those substances. Free radical-like substances in conjunction with macrophage-conditioned media produced toxic effect on mesothelial cells. The role of active oxygen radicals in fibre-induced carcinogenesis is discussed.     

循环肿瘤细胞自我种植对裸鼠骨肉瘤生长的促进作用

目的：通过建立骨肉瘤裸鼠荷瘤模型,观察骨肉瘤中是否存在循环肿瘤细胞自我种植现象,并探讨其在骨肉瘤进展中的作用。方法：建立骨肉瘤裸鼠原位荷瘤模型后,处理组尾静脉注射红色荧光蛋白（RFP）标记循环肿瘤细胞,对照组注射PBS,2周后将处理组原位瘤体冰冻切片荧光显微镜下观察有无自我种植,并根据肿瘤生长指标（大小、重量、生长曲线）将处理组与对照组进行比较分析。结果：处理组瘤体冰冻切片后荧光显微镜下观察发现,原位瘤组织中有红色荧光散在分布,即存在循环肿瘤细胞自我种植现象。肿瘤生长各指标比较发现,处理组瘤体在大小、重量、生长速率上均显著高于对照组（P〈0.05）,具有统计学意义。结论：骨肉瘤中存在循环肿瘤细胞自我种植现象,并且能够促进原位灶的生长。     

Contrasting effects of activated and nonactivated macrophages and macrophages from tumor-bearing mice on tumor growth in vivo

The effect of macrophages from normal and tumor-bearing mice on tumor growth was investigated with the use of an in vivo neutralization test. Macrophages from unstimulated and thioglycollate-stimulated peritoneal cavities (nonactivated macrophages) of normal mice enhanced growth of various syngeneic tumors [a 3-methylcholanthrene-induced transplantable fibrosarcoma from inbred C3HeB mice, a spontaneously originated transplantable melanoma (B16) from inbred C57BL/6 mice, and a radiation-induced lymphoma from inbred BALB/c mice]. This enhancing effect was not destroyed by irradiation of macrophages and was apparently mediated by macrophage secretory products. The effect appeared to be unrelated to immunosuppression and may have reflected direct stimulation of tumor cells. In contrast, Corynebacterium parvum-activated macrophages markedly inhibited tumor growth. Peritoneal macrophages from fibrosarcoma-bearing mice, which possessed tumor-inhibitory T-lymphocytes, enhanced tumor growth and abolished the effects of the tumor-inhibitory lymphocytes. Clearly, under certain conditions nonactivated macrophages interfered with the mechanisms of T-cell-mediated antitumor resistance in tumor-bearing mice.     

The role of photosensitized macrophages in photodynamic therapy

Cancer stimulates macrophage infiltration and encourages angiogenesis, which is necessary for tumor growth and invasion. It seems, that the influence of photodynamic therapy (PDT) on immune cells and immune regulators plays a crucial role in this process. In order to study this effect, the influence of δ-aminolevulinic acid (ALA) PDT on the activity of the murine macrophage J-774A.1 cell line was assessed. J-774A.1 cells were incubated with different concentrations of ALA and irradiated with a VIS light source (400-750 nm) at 5, 10 and 30?J/cm2. The effects of ALA-PDT were evaluated on the basis of cell viability and the secretory activity of macrophages (nitric oxide, NO; reactive oxygen intermediates, ROI; tumor necrosis factor α, TNF-α; interleukin-1β, IL-1β; and nuclear factor κB, NF-κB; proteins, p50 and p65). Experiments showed that at the higher energy doses, there was a large increase in ROI and TNF-α release and decreased levels of NF-κB p50 and p65, IL-1β production and NO release. The increased levels of ROI and TNF-α release after PDT could be an additional factor for the complete eradication of tumors. The decrease in NF-κB p50 and p65 and IL-1β levels could inhibit tumor progression.     

Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages

Genetic depletion of macrophages in Polyoma Middle T oncoprotein (PyMT)-induced mammary tumors in mice delayed the angiogenic switch and the progression to malignancy. To determine whether vascular endothelial growth factor A (VEGF-A) produced by tumor-associated macrophages regulated the onset of the angiogenic switch, a genetic approach was used to restore expression of VEGF-A into tumors at the benign stages. This stimulated formation of a high-density vessel network and in macrophage-depleted mice, was followed by accelerated tumor progression. The expression of VEGF-A led to a massive infiltration into the tumor of leukocytes that were mostly macrophages. This study suggests that macrophage-produced VEGF regulates malignant progression through stimulating tumor angiogenesis, leukocytic infiltration and tumor cell invasion.     

Glycolysis regulation in tumor-associated macrophages: Its role in tumor development and cancer treatment

Tumor-associated macrophages constitute the main cell population in the tumor microenvironment and play a crucial role in regulating the microenvironment composition. Emerging evidence has revealed that the metabolic profile determines the tumor-associated macrophage phenotype. Tumor-associated macrophage function is highly dependent on glucose metabolism, with glycolysis being the major metabolic pathway. Recent reports have demonstrated diversity in glucose flux of tumor-associated macrophages and complex substance communication with cancer cells. However, how the glucose flux in tumor-associated macrophages connects with glycolysis to influence tumor progression and the tumor microenvironment is still obscure. Moreover, while the development of single-cell sequencing technology allows a clearer and more accurate classification of tumor-associated macrophages, the metabolic profiles of tumor-associated macrophages from the perspective of single-cell omics has not been well summarized. Here, we review the current state of knowledge on glucose metabolism in tumor-associated macrophages and summarize the metabolic profiles of different tumor-associated macrophage subtypes from the perspective of single-cell omics. Additionally, we describe the current strategies targeting glycolysis in tumor-associated macrophages for cancer therapy.     

The role of the vascular phase in solid tumor growth: a historical review

Angiogenesis is a biological process by which new capillaries are formed from pre-existing vessels. It occurs in both physiological conditions such as embryo development, cyclically in the female genital system and during wound repair, and pathological conditions, such as arthritis, diabetic retinopathy and tumors. In solid tumor growth, a specific critical turning point is the transition from the avascular to the vascular phase. Having developed an intrinsic vascular network, the neoplastic mass is able to grow indefinitely (unlike all the other forms, tumor angiogenesis is not limited in time) both in situ and at distant sites (metastasis) in so far as an intrinsic vascular network enables its cells to enter the vascular bed and colonize other organs. Tumor angiogenesis depends mainly on the release by neoplastic cells of growth factors specific for endothelial cells and able to stimulate growth of the host's blood vessels. This review describes its history as traced by the main contributions to the international medical literature and their contents. The specific new paradigm discussed here has been gaining general approval and considerable confirmation, thanks to its possible applications, as recently highlighted by the introduction of anti-angiogenic substances in adjuvant tumor management.     

巨噬细胞在肺癌转移中的作用

转移是导致肺癌患者死亡的关键临床事件,目前针对转移高发人群仍缺乏有效的筛选与诊疗手段。免疫治疗显著提高晚期肺癌疗效,提示其有望突破肺癌转移防治的瓶颈。巨噬细胞作为固有免疫的重要组成部分,在肿瘤的发生与转移过程中发挥着重要作用,有望从固有免疫角度丰富肿瘤免疫治疗的手段。在肿瘤发生发展的不同阶段,巨噬细胞在机体的不同器官被肿瘤细胞驯化出不同的“状态”而有利于肿瘤的发展与转移。因此,靶向巨噬细胞防治肺癌转移成为肿瘤免疫治疗的新策略。靶向巨噬细胞的增殖、招募、极化、血管生成和免疫抑制等阶段,开发单克隆抗体及小分子抑制剂是抗肺癌转移新药研发的趋势。      

Effects on in vitro tumor growth of macrophages isolated from human ascitic ovarian tumors

Macrophages were isolated from 22 human ascitic ovarian epithelial tumors and their growth-inhibitory capacity was tested using as targets the following in vitro tumor cell lines: murlne TLX9 lymphoma and FS6 sarcoma; human myeloid K562 leukemia and human E cell line derived from an ovarian carcinoma. Macrophage preparations were heterogeneous in their interaction with tumor target cells, and assay conditions, such as the type of target cell, incubation time, and attacker to target cell (A:T) ratio critically affected the evaluation of the cytotoxic potential of tumor-associated macrophages. At an A:T ratio of 7:1 no cytostatic activity on TLX9 and K562 cells was ever observed, but in the presence of specific antibody 8 out of 12 macrophage preparations tested showed significant antibody-dependent cytotoxicity on TLX9 lymphoma cells. Macrophage preparations from two patients significantly inhibited growth of the FS6 sarcoma and a cytostatic activity on E cells was observed in five additional patients. Significant stimulation of the proliferative capacity of at least one of the target cell lines was observed in 11 subjects at an A:T ratio of 7:1. In 12 patients, macrophage cytostatic activity on E cells was also tested at an A:T ratio of 35:1; eight out of 12 preparations showed significant cytotoxicity under these conditions. When the same subject was repeatedly tested at short intervals the same pattern of inhibition or stimulation of tumor growth was observed.     

The role of recombinant epidermal growth factor and serotonin in the stimulation of tumor growth in a SCCHN xenograft model

One challenge of squamous cell carcinoma of the head and neck (SCCHN) chemotherapy is a small percentage of tumor cells that arrest in the G0?phase of the cell cycle and are thus not affected by chemotherapy. This could be one reason for tumor recurrence at a later date. The recruitment of these G0-arresting?cells into the active cell cycle and thus, proliferation, may increase the efficacy of chemotherapeutic agents. The aim of this study was to investigate whether stimulation with recombinant epidermal growth factor (EGF) or serotonin leads to an increased tumor cell proliferation in xenografts. Detroit?562?cells were injected into NMRI-Foxn1nu?mice. Treatment was performed with 15?μg murine or human EGF, or 200?μg serotonin. The control mice were treated with Lactated Ringer's solution (5?mice/group). Tumor size was measured on days?4, 8 and 12 after tumor cell injection. The EGF stimulated mice showed a significantly higher tumor growth compared to the serotonin-stimulated mice and the untreated controls. In the present study, we show that it is possible to stimulate tumor cells in xenografts by EGF and thus, enhance cell proliferation, resulting in a higher tumor growth compared to the untreated control group. In our future investigations, we plan to include a higher number of mice, an adjustment of the EGF dosage and cell subanalysis, considering the heterogeneity of SCCHN?tumors.     

The role of fibrin in tumor metastasis

Summary A volume of data that has accumulated for over a century has suggested that fibrin may facilitate the persistence and progression of malignancy. Techniques that have been developed recently have shown that fibrin is indeed a component of the connective tissue stroma in human malignancy but in only a few tumor types. However, therapeutic intervention studies with drugs that limit thrombin activity or enhance fibrinolysis have shown favorable clinical effects in at least one such tumor type. These favorable findings affirm the concept that cause-and-effect relationships do, in fact, exist between thrombin generation with fibrin formation and tumor progression, and suggest that a rational basis exists for the design of future drug intervention trials that target reactions relevant to specific tumor types. These findings also provide a basis for the design of experiments capable of defining further the role of fibrin in the integrity of these tumor types. Because fibrinogen is found much more commonly than fibrin in the connective tissue of a variety of human malignancies, attention might reassumably be directed to determining the possible contribution of this molecule as well as of fibrin to tumor progression.