Growth hormone in the tumor microenvironment

ABSTRACT Tumor development is a multistep process whereby local mechanisms enable somatic mutations during preneoplastic stages. Once a tumor develops, it becomes a complex organ composed of multiple cell types. Interactions between malignant and non-transformed cells and tissues create a tumor microenvironment (TME) comprising epithelial cancer cells, cancer stem cells, non-tumorous cells, stromal cells, immune-inflammatory cells, blood and lymphatic vascular network, and extracellular matrix. We review reports and present a hypothesis that postulates the involvement of growth hormone (GH) in field cancerization. We discuss GH contribution to TME, promoting epithelial-to-mesenchymal transition, accumulation of unrepaired DNA damage, tumor vascularity, and resistance to therapy. Arch Endocrinol Metab. 2019;63(6):568-75

Promoting inflammatory lymphangiogenesis by vascular endothelial growth factor-C (VEGF-C) aggravated intestinal inflammation in mice with experimental acute colitis

Angiogenesis and lymphangiogenesis are thought to play a role in the pathogenesis of inflammatory bowel diseases (IBD). However, it is not understood if inflammatory lymphangiogenesis is a pathological consequence or a productive attempt to resolve the inflammation. This study investigated the effect of lymphangiogenesis on intestinal inflammation by overexpressing a lymphangiogenesis factor, vascular endothelial growth factor-C (VEGF-C), in a mouse model of acute colitis. Forty eight-week-old female C57BL/6 mice were treated with recombinant adenovirus overexpressing VEGF-C or with recombinant VEGF-C156S protein. Acute colitis was then established by exposing the mice to 5% dextran sodium sulfate (DSS) for 7 days. Mice were evaluated for disease activity index (DAI), colonic inflammatory changes, colon edema, microvessel density, lymphatic vessel density (LVD), and VEGFR-3mRNA expression in colon tissue. When acute colitis was induced in mice overexpressing VEGF-C, there was a significant increase in colonic epithelial damage, inflammatory edema, microvessel density, and neutrophil infiltration compared to control mice. These mice also exhibited increased lymphatic vessel density (73.0±3.9 vs 38.2±1.9, P<0.001) and lymphatic vessel size (1974.6±104.3 vs 1639.0±91.5, P<0.001) compared to control mice. Additionally, the expression of VEGFR-3 mRNA was significantly upregulated in VEGF-C156S mice compared to DSS-treated mice after induction of colitis (42.0±1.4 vs 3.5±0.4, P<0.001). Stimulation of lymphangiogenesis by VEGF-C during acute colitis promoted inflammatory lymphangiogenesis in the colon and aggravated intestinal inflammation. Inflammatory lymphangiogenesis may have pleiotropic effects at different stages of IBD.

Angiogenesis in the progression of cutaneous squamous cell carcinoma: an immunohistochemical study of endothelial markers

OBJECTIVE: To demonstrate the role of angiogenesis in the progression of cutaneous squamous cell carcinoma. INTRODUCTION: Angiogenesis is a pivotal phenomenon in carcinogenesis. Its time course in cutaneous squamous cell carcinoma has not yet been fully established. METHODS: We studied the vascular bed in 29 solar keratoses, 30 superficially invasive squamous cell carcinomas and 30 invasive squamous cell carcinomas. The Chalkley method was used to quantify the microvascular area by comparing panendothelial (CD34) with neoangiogenesis (CD105) immunohistochemical markers. The vascular bed from non-neoplastic adjacent skin was evaluated in 8 solar keratoses, 10 superficially invasive squamous cell carcinomas and 10 invasive squamous cell carcinomas. RESULTS: The microvascular area in CD105-stained specimens significantly increased in parallel with cutaneous squamous cell carcinoma progression. However, no differences between groups were found in CD34 sections. Solar keratosis, superficially invasive squamous cell carcinoma and invasive squamous cell carcinoma samples showed significant increases in microvascular area for both CD34- and CD105-stained specimens compared with the respective adjacent skin. DISCUSSION: The angiogenic switch occurs early in the development of cutaneous squamous cell carcinoma, and the rate of neovascularization is parallel to tumor progression. In contrast to panendothelial markers, CD105 use allows a dynamic evaluation of tumor angiogenesis. CONCLUSION: This study demonstrated the dependence of skin carcinogenesis on angiogenesis.

Remodelamento das vias aéreas inferiores e superiores: [revisão] / Remodeling of the lower and upper airways: [revision]

Remodelamento pode ser definido como modelar novamente ou de forma diferente, reconstruir. Trata-se de um aspecto crítico do processo de reparação de lesões em todos os órgãos, representando um evento dinâmico de produção e degradação de matriz, em reação a inflamação, levando à reconstrução normal do tecido ou à formação de um tecido patológico. OBJETIVO E MÉTODO: Comparar os dados existentes em literatura entre o remodelamento de vias aéreas inferiores e superiores. RESULTADO: Asma é uma doença inflamatória crônica associada a remodelamento de vias aéreas. Na rinite alérgica, outra doença inflamatória crônica, o remodelamento é ainda pouco entendido. Apesar de a inflamação ser similar na rinite alérgica e asma, a extensão patológica do remodelamento nasal, assim como sua repercussão clínica, pode ser diferente dos brônquios. CONCLUSÃO: O remodelamento nas vias aéreas superiores ocorre em menor intensidade que nas vias inferiores, mas é aparente que a estrutura da mucosa nasal de pacientes com rinite não é normal.

Remodeling is defined as modeling again or differently, as reconstructing. Remodeling is a critical aspect of wound repair in all organs; it represents a dynamic process that associates the production and degradation of matrix in reaction to inflammation. This leads to normal reconstruction or a pathologic process. AIM AND METHODS: To compare data in the current literature on upper and lower airways. RESULTS: Asthma is a chronic inflammatory disease associated with abnormal airways remodeling. In allergic rhinitis, another chronic inflammatory disease, remodeling is still poorly understood. Even though inflammation is similar in allergic rhinitis and asthma, the pathologic extent of nasal remodeling, as well as its clinical consequences, might be different from those in bronchi. CONCLUSION: Remodeling occurs less in upper airways compared to lower airways; it is apparent, however, that the structure of the rhinitic nose is not normal.

Avaliação da perimetria macular em pacientes com degeneração macular relacionada à idade por meio do oftalmoscópio de rastreamento a laser / Evaluation of macular perimetry in patients with age-related macular degeneration using the scanning laser ophthalmoscope

OBJETIVOS: Verificar a relação entre alterações anatômicas (drusas duras, drusas moles, hiperpigmentação, neovasos, descolamento do epitélio pigmentado da retina, hipopigmentação e atrofia coriorretiniana) e a sensibilidade à luz em pacientes com degeneração macular relacionada à idade (DMRI); analisar a sensibilidade macular em áreas com ausência de lesões anatômicas nos pacientes com DMRI comparando-as ao grupo de controles, para avaliar a existência ou não de lesão funcional em área sem lesão anatômica. MÉTODOS: Estudo comparativo, descritivo e analítico, de corte transversal. O grupo de casos foi formado por 31 indivíduos portadores de DMRI com idade entre 51 e 88 anos. O grupo de controles ficou composto por 31 indivíduos considerados "sadios", não portadores de DMRI com idade entre 61 e 80 anos. Os grupos foram pareados por sexo e idade. Realizou-se a perimetria macular estática, vermelho-vermelho, com o oftalmoscópio de rastreamento a laser (ORL). Os resultados da perimetria macular foram correlacionados à lesão anatômica identificada no local correspondente pelo laser infravermelho e fotografias coloridas. RESULTADOS: As áreas com neovasos ou atrofia apresentaram sensibilidade significantemente diferente em relação às áreas com ausência de lesões anatômicas nos pacientes com DMRI. Houve perda funcional significativa em áreas com ausência de lesões anatômicas nos pacientes com DMRI em relação ao grupo de controles. CONCLUSÕES: Áreas com neovasos ou atrofia podem ser fatores individuais de piora da sensibilidade macular localizada. Pode ocorrer perda funcional mesmo sem lesão anatômica aparente nos pacientes com DMRI.

PURPOSES: To evaluate the correlation between anatomical changes (hard druses, soft druses, hyperpigmentation, new vessels, detachment of retinal pigment epithelium, hypopigmentation and chorioretinal atrophy) and light sensitivity in patients with age-related macular degeneration (ARMD); analyze macular sensitivity in areas with no anatomical lesions in patients with ARMD and compared them to the control group in order to detect if there was any functional lesion in areas with no anatomical changes. METHODS: A cross-sectional, comparative, descriptive and analytic study was performed. The case group consisted of 31 subjects with ARMD aged between 51 and 88 years. The control group consisted of 31 "healthy" subjects, without ARMD aged between 61 and 80 years. The groups were matched for gender and age. We performed static macular perimetry, red-red, using a scanning laser ophthalmoscope (SLO). Results of macular perimetry were correlated with the anatomic lesion identified in the same site by infrared laser and color photographs. RESULTS: Areas with new vessels or atrophy showed a significantly different sensitivity in relation to areas without anatomical lesions in patients with ARMD. There was significant functional loss in areas with no anatomical lesions in patients with ARMD in relation to the control group. CONCLUSIONS: Areas with new vessels or atrophy could be distinct factors for worsening of the localized macular sensitivity. There might be functional loss even in areas with no apparent anatomical changes in ARMD patients.

La proteína quimiotratante de monocitos correlaciona con la angiogénesis en melanomas metastásicos / Monocyte chemoattractante protein correlates with angiogenesis in metastatic melanoma

Se analizaron biopsias de melanoma metastásico humano para elucidar la relación entre la expresión de la quimioquina MCP-1/CCL2 (monocyte chemoattractant protein-1), la angiogénesis y la agrasividad del tumor. Se encontró que esta quimioquina se expresa en el 100% de los casos, con heterogeneidad en el porcentaje de células positivas dentro del tumor. Estos tumores presentaron gran cantidad de macrófagos infiltrantes, particularmente asociados a las áreas de mas activa angiogénesis. Se obtuvo correlación positiva entre el porcentaje de células que expresan MCP-1 y el grado de vascularización. Asimismo, se encontró asociación entre una mayor angiogénesis y la proliferación tumoral evaluada como índice mitótico. Estos resultados sugieren que el aumento en la vascularización podría ser predictivo de metástasis más agresivas, donde la expresión de MCP-1 estaría estrechamente vinculada al desarrollo de vasos a través del reclutamiento de macrófagos.

Computational Analysis of Tumor Angiogenesis Patterns Using a Two-dimensional Model

Tumor angiogenesis was simulated using a two-dimensional computational model. The equation that governed angiogenesis comprised a tumor angiogenesis factor (TAF) conservation equation in time and space, which was solved numerically using the Galerkin finite element method. The time derivative in the equation was approximated by a forward Euler scheme. A stochastic process model was used to simulate vessel formation and vessel elongation towards a paracrine site, i.e., tumor-secreted basic fibroblast growth factor (bFGF). In this study, we assumed a two-dimensional model that represented a thin (1.0mm) slice of the tumor. The growth of the tumor over time was modeled according to the dynamic value of bFGF secreted within the tumor. The data used for the model were based on a previously reported model of a brain tumor in which four distinct stages (multicellular spherical, first detectable lesion, diagnosis, and death of the virtual patient) were modeled. In our study, computation was not continued beyond the 'diagnosis' time point to avoid the computational complexity of analyzing numerous vascular branches. The numerical solutions revealed that no bFGF remained within the region in which vessels developed, owing to the uptake of bFGF by endothelial cells. Consequently, a sharp declining gradient of bFGF existed near the surface of the tumor. The vascular architecture developed numerous branches close to the tumor surface (the brush-border effect). Asymmetrical tumor growth was associated with a greater degree of branching at the tumor surface.

Effects of TNF-alpha on Angiogenesis in CT-26 Mouse Colon Carcinoma Homograft Model / 대한소화기학회지

BACKGROUND/AIMS: Tumor necrosis factor-alpha (TNF-alpha) exerts its anti-tumor effect through direct cytotoxicity on tumor cells and damage to the tumor vasculature. However, its role in tumor angiogenesis is controversial. We evaluated the angiogenic effect of TNF-alpha on BALB/c mouse colon carcinoma homograft model. METHODS: Ten BALB/c mice were inoculated intraperitoneally with CT-26 mouse colon carcinoma cells. After a week, recombinant mouse TNF-alpha (2microgram/mL) were given four times on every other day to five animals and the same volume of phosphate buffered saline was given at the same interval to five animals as control. Harvested tumor tissues were stained by immunohistochemistry with CD31 and VEGF antibodies. Number of microvessels and VEGF expression were counted by light microscope. RESULTS: The mean microvessel counts per 200x field of TNF-alpha treated animals were 70.2+/-7.8 and those of nontreated animals were 83.8+/-8.3 (p<0.05). The VEGF score of both groups were 3. CONCLUSIONS: TNF-alpha treated animals showed decreased microvessel counts in tumor tissue but VEGF expression in both groups showed no difference. Therefore, TNF-alpha showed antiangiogenic effects on colon carcinoma homograft model.

Angiogenese, fator de crescimento endotelial vascular e endometriose / Angiogenesis, vascular endothelial growth factor and endometriosis

A endometriose correlaciona-se com diversos processos imunologicos entre eles a angiogenese. Dentre os fatores que promovem este processo, o fator de...

Metaloproteinasas como marcadores de progresión tumoral y futuros blancos de terapias en patologías linfoides / Metalloproteinases as markers of tumoral progression and future targets for therapies in neoplasms of lymphoid tissue

En las últimas décadas la medicina evolucionó hacia un enfoque molecular en la búsqueda de blancos específicos que permitan seguir adecuadamente la progresión de las patologías neoplásicas y desarrollar terapias exitosas. El conocimiento y comprensión de que la matriz extracelular (MEC) que rodea a un tumor influye sobre el comportamiento del mismo, reveló la importancia que cumplen las metaloproteinasas (MMPs) en la regulación de los componentes de la MEC, y por lo tanto en el desarrollo tumoral. Es por ello que actualmente se está evaluando la eficacia de inhibidores sintéticos de estas enzimas en ensayos clínicos, algunos ya en fase clínica III de investigación. También se propone que estas MMPs podrían ser utilizadas como marcadores bioquímicos, permitiendo evaluar la progresión de la enfermedad en pacientes que sufren patologías neoplásicas, e incluso dar un valor pronóstico. Es en este punto en que el laboratorio de análisis clínicos cumplirá un papel fundamental y deberá contar con los conocimientos y las herramientas necesarias para evaluar la presencia y actividad de estas enzimas. En este trabajo se expone el conocimiento actual de la estructura y funciones biológicas de las MMPs así como los antecedentes que muestran el papel que cumplen en las enfermedades neoplásicas, en especial en leucemias y linfomas

Targeting angiogenesis -- a novel mode in cancer chemoprevention.

Cancer prevention is fast emerging as a discipline with a promising potential. Chemoprevention has its rationale in the multistage process of carcinogenesis which provides an option for development of preventive approaches in the early, premalignant stages, before appearance of clinical symptoms. Evidence is mounting that the angiogenic switch may be an early event in carcinogenesis. Most chemopreventive agents currently under development probably act via multiple mechanisms. The chemopreventives used in clinical trials, such as nonsteroidal anti-inflammatories, tamoxifen and retinoids, have been shown to inhibit angiogenesis, the formation of new vessels from existing vasculature, which may contribute to their protective effect. Development and use, alone or in combination with other agents with other mechanisms of action, of specific antiangiogenic agents is likely to open new possibilities in cancer chemoprevention.

Talidomida en cáncer avanzado: estudio en fase I / Thalidomide in advanced cancer: aphase I study

Antecedentes: en 1997, en México se registraron más de 87 mil casos nuevos de cáncer. Las neoplasias más frecuentes fueron: cuello uterino, mama, próstata, ganglios linfáticos y estómago. La angiogénesis es un factor determinante en el crecimiento y proliferación neoplásica, así como para conferir la capacidad metastásica tumoral. La talidomida, que fue vinculada con teratogénesis en los años 50, tiene capacidad de inhibir la angiogénesis, inducir la apoptosis y tiene efectos inmunomoduladores. Objetivo: evaluar la tolerancia y seguridad de la talidomida como agente antiangiogénico, en pacientes con neoplasia avanzada. Pacientes y método: mayores de 18 años, de uno y otro sexos, con neoplasia metastásica multitratada, con resistencia o progresión a terapia convencional, que recibieron talidomida como monoterapia al menos durante un mes. Este fármaco fue administrado a dosis de 100 mg/día, vía oral con ascenso a 200 mg la primera semana y luego cada 15 días hasta 800 mg. Se evaluaron edad, sexo, neoplasia y estirpe histológica, etapa clínica, dosis utilizada, tiempo de uso, efectos secundarios y tiempo de seguimiento. Resultados: 13 pacientes, 3 mujeres y 10 hombres, edad promedio 57.8 + 14.6 años margen de 31 a 76. Correspondían a: 10 tumores sólidos y 3 hematológicos. Se incluyeron 3 hepatocarcinoma, 2 mieloma múltiple, 2 melanoma, 2 pulmón y uno de mama, colon, recto y linfoma no Hodgkin. De las 10 sólidas, 7 en EC IV y 3 EC III; en las hematológicas, 2 etapa II de Durie-Salmon y el linfoma en etapa IV. Ocho pacientes tenían evidencia de actividad metastásica, 61.5 por ciento. Cinco pacientes habían recibido 1 línea de quimioterapia, otros 6 pacientes 2 y 3 más de 3 esquemas. Dosis de talidomida: 4 pacientes emplearon 100 mg/día; 7, 200 mg; 1, 300 mg y 1, 400 mg/día, sólo en 2 pacientes se intentó escalar la dosis. El tiempo promedio de uso 3.15 + 3.8 meses, margen de 1 a 12, mediana 1. Diez pacientes tuvieron efectos secundarios; somnolencia, 8; 6 neuropatía periférica sensitiva, 1 erupción cutánea. Se observaron casos con estabilidad de la enfermedad durante al menos dos meses y ocho casos con progresión. La talidomida fue adecuadamente tolerada a la dosis de 100 a 200 mg/día, su uso se asocia con somnolencia y neuropatía periférica sensitiva de bajo grado, los efectos secundarios se incrementan al elevar la dosis. Se requiere de más estudios para evaluar su efecto antitumoral, dosis óptima y su asociación con quimioterapia o agentes inmunomoduladores

Clinical significance of microvessel density in multiple myeloma patients

To investigate the role of angiogenesis in multiple myeloma (MM), bone marrow biopsy from 75 adults with newly diagnosed, untreated MM were evaluated. Microvessels were scored in at least 3 areas ( x 200 fields) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for CD34. Prognostic variables were also evaluated for the overall survival. Microvessel counts were significantly higher in patients with MM (n=69.42+/-9.67), compared with control (n=26.81+/-2.85). Microvessel density had a weak correlation with percentage of bone marrow plasma cells. By univariate analysis, age, beta2-microglobulin, serum albumin, serum creatinine, serum calcium, hemoglobin, platelet count, and bone marrow plasma cell percentage were correlated with survival. By multivariate analysis, age, serum albumin, serum creatinine, hemoglobin, platelet count and bone marrow plasma cell percentage were correlated with overall survival, whereas microvessel density was not. In summary, microvessel density in bone marrow of MM is significantly increased compared to control, but was not correlated with overall survival. Further studies regarding angiogeneic molecules are needed to determine the functional role of angiogenesis in MM.

Angiogênese no carcinoma colorretal - revisäo e perspectivas / Colorectal carcinoma angiogenisis - review and perspectives

Em adiçäo aos sistemas de estadiamento clinicopatológicos comumente utilizados, fatores de risco para a recorrência no carcinoma colorretal têm sido investigados. Entre estes a quantificaçäo da angiogênese e de peptídeos angiogênicos têm demonstrado aplicaçäo clínica na avaliaçäo da sobrevida e recorrência. A angiogênese é o crescimento de novos capilares, estando associada tanto ao desenvolvimento tecidual pré e pós-natal, cicatrizaçäo e reproduçäo como em doenças inflamatórias e neoplasias. Além de permitir o crescimento tumoral, evidências experimentais demonstram que a angiogênese associa-se com o processo metastático, pois maior é a superfície vascular para o escape de células neoplásicas, o que também pode ser facilitado pela imaturidade dos novos vasos. Neste artigo de revisäo discute-se o processo de formaçäo de vasos capilares, associado ao crescimento tumoral e ao surgimento de metástases hematogênicas, bem como uma revisäo de literatura abordando angiogênese e carcinoma colorretal e o seu papel como um possível alvo terapêutico

Expression of leptin receptor (Ob-R) in human atherosclerotic lesions: potential role in intimal neovascularization

Neovascularization of the adventitial vasa vasorum with extension into the intima of atherosclerotic lesions is frequently observed, but its pathophysiological significance is still subject to debate. Recently, leptin, the product of the Ob gene, was identified. Leptin, via activation of the endothelial receptor (Ob-R), generates a growth signal involving a tyrosine kinase-dependent intracellular pathway and promotes angiogenic processes. We hypothesized that a high concentration of leptin within vasa vasorum and plaque itself, may influence inflammatory and vascular neovascularization coupling with functional upregulation of the vascular endothelial growth factor (VEGF). Microscopic computerized tomography was utilized for the spatial distribution of vasa vasorum and intimal neovascularization from atherosclerotic human coronary arteries. Atherosclerotic coronary arteries showed a dense plexus of microvessels in the adventitia and plaque itself. Microscopic analysis from human atherosclerotic aortas revealed an increase in the intimal thickness with neovascularization. The immunoreactivity for Ob-R, VEGF and matrix metalloproteinase (MMP) increased in atherosclerotic plaque, predominantly in the endothelial lining of the intimal neovessel and macrophages/foam cells. Our observation of a prominent colocalization between Ob-R, VEGF and MMP supports this hypothesis and these factors participate in the neovascularization of atherosclerotic lesions. The present study is the first report on vascular tissue and it opens a promising perspective concerning future investigations of leptin-dependent modulation of atherogenesis and vascular neovascularization under pathophysiolgical conditions.

Angiogénesis en el carcinoma del colon y del recto / Angiogenesis in colo-rectal carcinoma

Objetivo: Investigar la angiogénesis, uno de los factores involucrados en el desarrollo neoplásico y analizar su relación fisiopatogénica en el carcinoma del colon y del recto. Lugar de aplicación: Hospital Español de Buenos Aires. Diseño: Estudio retrospectivo y descriptivo. Población: 43 pacientes operados por carcinoma del colon y del recto, entre Enero de 1995 y Diciembre de 1997. De ellos, 29 eran del sexo femenino y 15 del masculino. Edad promedio 71 años, con rango de 34 a 92 años. Método: Se efectuaron cortes histológicos de los tumores que fueron teñidos con anticuerpos monoclonales anti CD 31, anti CD 34 y policlonal factor VIII o de von Willebrand. Se analizó la densidad de la microvasculatura (DMC) y se la correlacionó con el grado histológico, la presencia de ganlios metastásicos, el tamaño y la estadificación tumoral. Para la estadificación se utilizó la clasificación de Dukes modificándola con el agregado de la letra "D" cuando hubo diseminación a distancia. Resultados: 2 pacientes tenían estadio A, 19 estadio B, 18 estadio C y 4 estadio D. Hubo correlación estadísticamente significativa entre la angiogénesis y las adenopatías metastásicas (CD 31 p=0.006; CD 34 p=0.0002 y FVIII p=0.00008) y con la diferenciación histológica (CD 31 p- 0.00008; CD 34 p= 0.000002 y F VIII p=0.005). No hubo correlación estadísticamente significativa con el tamaño tumoral ni con la estadificación de las neoplasias. Conclusiones: La presencia de metástasis ganglionares y el grado de diferenciación tumoral se correlacionaron con una mayor densidad de la microvasculatura, lo que sugiere la importancia de la angiogénesis en la fisiopatogenia del carcinoma colorrectal.