Infiltration of thymidine phosphorylase-positive macrophages is closely associated with tumor angiogenesis and survival in intestinal type gastric cancer

Kawahara, Akihiko; Hattori, Satoshi; Akiba, Jun; Nakashima, Kenichiro; Taira, Tomoki; Watari, Kosuke; Hosoi, Fumihito; Uba, Manami; Basaki, Yuji; Koufuji, Kikuo; Shirouzu, Kazuo; Akiyama, Shin Ichi; Kuwano, Michihiko; Kage, Masayoshi; Ono, Masahiro

doi:10.3892/or_00000873

Cited by 50 publications

(53 citation statements)

References 25 publications

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“…Stage of Human Gastric Cancers-TAMs are associated with poor prognosis in gastric cancer (36). To provide some information regarding EGFR in macrophages in human cancers, we sought to study whether there is a correlation between the level of EGFR expression in macrophages in cancer tissues and tumor development.…”

Section: Expression Of Egfr In Macrophages Is Decreased In the Latementioning

confidence: 99%

Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth

Zhao

Liu

Peek

et al. 2016

Journal of Biological Chemistry

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EGF receptor (EGFR) in tumor cellsMacrophages contribute to immune responses through possessing phenotypic plasticity. Classically activated macrophages (M1 polarization) are driven by IFN-␥ and pathogenderived signals, such as LPS-activated canonical interferon-regulatory factor-3 (IRF-3) and STAT1 pathways. Macrophages with M1 polarization are characterized by production of proinflammatory cytokines and NOS2 (1). Alternatively activated macrophages (M2 polarization) are elicited by IL-4-and IL-13-activated STAT6 and IL-10-activated STAT3 signals. M2-polarized macrophages exhibit increased transcription of genes, including arginase 1 (Arg1), 4 mannose receptor 1 (Mrc1), resistin-like ␣ (Retnla, Fizz1), and chitinase 3-like 3 factor (Chi3l3, YM1) (1) and possess functions of antiinflammation, angiogenesis, and tissue repair, thus having tumor-promoting properties (1, 2). In addition, other transcriptional factors, such as NF-B (3) and IL-4-induced epigenetic changes (4) have been found to participate in directing polarization in macrophages.Tumor-associated macrophages (TAMs) in the tumor microenvironment usually exhibit M2 polarization in human and mouse models of cancers (5, 6) and possess pro-tumorigenic activities in most cancers, including promoting tumor cell proliferation, migration, and invasion, increasing angiogenesis, and suppressing immunity through secretion of growth factors such as HB-EGF, EGF, CSF-1, VEGF, and PDGF, enzymes, including metalloproteinases (MMPs), and cytokines, such as IL-6, IL-10, and TNF (7). Clinical studies have revealed that * This work was supported, in whole or in part, by National Institutes of Health Grants R01DK081134 (to F. Y.) and R01DK56008 and R01DK54993 (to D. B. P.), and core services were performed through Vanderbilt University Medical Center's Digestive Disease Research Center supported by National Institutes of Health Grant P30DK058404. This work was also supported by National Natural Science Foundation of China Grant 31471341 (to H. L.)The authors declare no conflict of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 4 The abbreviations used are: Arg1, arginase 1; TAM, tumor-associated macrophage; MMP, metalloproteinase; EGFR, EGF receptor; EMT, epithelial-mesenchymal transition; SOCS1, suppressor of cytokine signaling 1; IMCE, Immorto-Min colonic epithelial.

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Section: Expression Of Egfr In Macrophages Is Decreased In the Latementioning

confidence: 99%

Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth

Zhao

Liu

Peek

et al. 2016

Journal of Biological Chemistry

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“…TAMs, in particular, have been found to be associated with tumor growth and metastasis (5)(6)(7). A large number of studies concerning numerous tumor types, including colorectal cancer (5), supraglottic laryngeal carcinoma (6), Ewing's sarcoma (7), intestinal type gastric cancer (29), pancreatic cancer (30), non-gynecologic leiomyosarcoma (31) and thyroid cancer (32), have shown that the presence of TAMs in the tumor microenvironment is associated with a worse prognosis. Therefore, TAMs play an important role in tumor progression.…”

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confidence: 99%

Urotensin II contributes to the formation of lung adenocarcinoma inflammatory microenvironment through the NF-κB pathway in tumor-bearing nude mice

et al. 2012

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Abstract. Urotensin II (UII), a somatostatin-like cyclic peptide, was originally isolated from the fish urophysis. Our previous study showed that UII stimulates the proliferation of A549 lung adenocarcinoma cells and promotes tumor growth in a nude mouse xenograft model, suggesting that UII may contribute to the pathogenesis of lung adenocarcinoma. In this study, the underlying mechanism for UII to promote lung adenocarcinoma growth was explored by observing the effect of UII on the tumor inflammatory microenvironment in tumor-bearing nude mice. Immunohistochemical analysis showed that UII promoted the infiltration of CD68 + tumor-associated macrophages (TAMs) in the tumor microenvironment. Enzyme-linked immunosorbent assay (ELISA) demonstrated that UII promoted the release of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-9 (MMP-9). Western blot analysis showed that UII promoted the activation of nuclear factor-κB (NF-κB). These findings suggest that the enhanced levels of IL-6, TNF-α and MMP-9 in the tumor microenvironment, which likely resulted from increased activation of NF-κB induced by UII, may be one of the important mechanisms by which UII promotes lung adenocarcinoma growth. These findings imply that antagonists of UII or urotensin II-receptor (UT-R) have potential for the prevention and treatment of lung adenocarcinoma. IntroductionSeveral lines of evidence have suggested a strong association between chronic inflammation and carcinogenesis (1-4). It has been estimated that up to 20% of all tumors arise from the sites of infection, chronic irritation and inflammation (1). Persistent stimulation of chronic inflammation may cause the infiltration of inflammatory cells, the release of cytokines and the production of reactive oxygen species, which results in DNA damage, angiogenesis, tumor invasion and metastasis (1). There are numerous types of inflammatory cells in the tumor microenvironment, and tumor-associated macrophages (TAMs) are a major component. While the role of TAMs in tumor development is complex and multifaceted, in clinical studies, increased TAM density has been found to be associated with poor prognosis (5-7). TAMs contribute to tumor development through several mechanisms, including releasing angiogenic factors, promoting tumor cell proliferation, and facilitating tumor cell invasion and metastasis (8).Lung cancer is one of the models of inflammation-driven carcinogenesis (9,10). It has been shown that chronic exposure to tobacco smoke is the major risk factor for development of lung cancer by inducing inflammation (11,12). Takahashi et al (13) further demonstrated that tobacco smoke promotes lung tumorigenesis by triggering IKKβ-and JNK1-dependent inflammation. Moreover, regular use of nonsteroidal antiinflammatory drugs decreases the risk of lung cancer (14,15). Therefore, inflammation plays an important role in lung carcinogenesis.Urotensin II (UII), a somatostatin-like cyclic peptide, was originally isolated from the fish urophysis (16). Subseque...

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“…Однако большинство исследова-ний свидетельствует о том, что высокая плотность макрофагов связана с факторами неблагоприятного прогноза и ухудшением отдаленных результатов лечения больных раком желудка [33,80,81].…”

Section: Foxp3unclassified

Modern concepts of factors for gastric cancer progression

Сеньчукова¹,

Ryabov²

2016

Onkol. Z. im. P.A. Gercena

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82Рак желудка продолжает оставаться одним из самых распро-страненных злокачественных заболеваний в мире [1, 2]. В Рос-сийской Федерации в 2013 г. в структуре онкологической заболе-ваемости эта патология заняла 4-е место (8,8%) у мужчин и 5-е (5,7%) у женщин [3]. Несмотря на определенную тенденцию к снижению заболеваемости раком желудка в большинстве стран мира [1, 3], результаты лечения этой патологии нельзя считать удовлетворительными. В структуре смертности от злокачествен-ных новообразований рак желудка прочно занимает 2-е место [3, 4]. Это связано с тем, что более 70% больных впервые обращают-ся за медицинской помощью, уже имея III или IV стадию заболе-вания. Как следствие, летальность от рака желудка в течение первого года после установления диагноза составляет около 50% [5], а 5-летняя выживаемость радикально оперированных боль-ных в большинстве стран мира не превышает 15-30% [2, 4]. В связи с этим определение факторов, способствующих прогрес-сии рака желудка, чрезвычайно важно как для прогнозирования течения заболевания, планирования адекватной терапии, так и для поиска новых направлений в лечении этой патологии.Целью настоящего обзора явилось освещение важнейших клинико-морфологических и молекулярно-биологических фак-торов, определяющих прогноз и течение рака желудка.Согласно данным японского общества по изучению рака, стадия заболевания, гистологическая структура опухоли, лимфа-тическая и венозная инвазия являются ведущими клинико-мор-фологическими факторами прогноза рака желудка [6, 7]. Наибо-лее низкие показатели выживаемости отмечены при глубине ин-вазии Т3 и Т4; при наличии метастазов в регионарных лимфати-ческих узлах, особенно при N2 и N3; при наличии лимфатиче-ской и венозной инвазии; при низкодифференцированной и му-цинозной аденокарциноме, недифференцированном и желези-сто-плоскоклеточном раке; диффузно-инфильтративном и ин-фильтративно-язвенном раке желудка [6, 7].Следует отметить, что при отсутствии отдаленных метаста-зов решающее значение для прогноза имеет поражение регио-нарных лимфатических узлов. Значение имеет не только наличие метастазов, но и количество пораженных лимфатических узлов, их локализация [8][9][10][11]. Риск лимфогенного метастазирования повышается с увеличением размера и глубины инвазии опухоли [8, 9, 12, 13] при диффузном типе рака желудка, низкодифферен-цированных и недифференцированных опухолях [14,15], при на-личии лимфатической и венозной инвазии [8, 9, 13,16].Ухудшение отдаленных результатов лечения отмечено при локализации опухоли в проксимальной трети желудка [7,17,18] и у лиц молодого возраста [19,20]. Ухудшение выживаемости у мо-лодых пациентов связывают с преобладанием у них диффузных и недифференцированных опухолей (68% против 25% у пожилых), более частой проксимальной локализацией опухоли и более рас-пространенными стадиями заболевания. представлен обзор клинических, морфологических, молекулярно-биологических факторов, ассоциированных с прогрес-сией рака желудка. особое внимание уделено роли ангиогенеза и воспаления в инициации процессов инвазии и мета-стаз...

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Infiltration of thymidine phosphorylase-positive macrophages is closely associated with tumor angiogenesis and survival in intestinal type gastric cancer

Cited by 50 publications

References 25 publications

Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth

Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth

Urotensin II contributes to the formation of lung adenocarcinoma inflammatory microenvironment through the NF-κB pathway in tumor-bearing nude mice

Modern concepts of factors for gastric cancer progression

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