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

Alternagin-C binding to 21 integrin controls matrix metalloprotease-9 and matrix metalloprotease-2 in breast tumor cells and endothelial cells

Background Matrix metalloproteinases (MMPs) are key players in tumor progression, helping tumor cells to modify their microenvironment, which allows cell migration to secondary sites. The role of integrins, adhesion receptors that connect cells to the extracellular matrix, in MMP expression and activity has been previously suggested. However, the mechanisms by which integrins control MMP expression are not completely understood. Particularly, the role of 21 integrin, one of the major collagen I receptors, in MMP activity and expression has not been studied. Alternagin-C (ALT-C), a glutamate-cysteine-aspartate-disintegrin from Bothrops alternatus venom, has high affinity for an 21 integrin. Herein, we used ALT-C as a 21 integrin ligand to study the effect of ALT-C on MMP-9 and MMP-2 expression as well as on tumor cells, fibroblats and endothelial cell migration. Methods ALT-C was purified by two steps of gel filtration followed by anion exchange chromatography. The 21, integrin binding properties of ALT-C, its dissociation constant (Kd) relative to this integrin and to collagen I (Col I) were determined by surface plasmon resonance. The effects of ALT-C (10, 40, 100 and 1000 nM) in migration assays were studied using three human cell lines: human fibroblasts, breast tumor cell line MDA-MB-231, and microvascular endothelial cells HMEC-1, considering cells found in the tumor microenvironment. ALT-C effects on MMP-9 and MMP-2 expression and activity were analyzed by quantitative PCR and gelatin zymography, respectively. Focal adhesion kinase activation was determined by western blotting. Results Our data demonstrate that ALT-C, after binding to 21 integrin...

Carcinoma de células escamosas de cabeça e pescoço (HNSCC): desvendando os mistérios do microambiente tumoral / Head and neck squamous cell carcinoma (HNSCC): unmasking the tumor microenvironment

Este artigo refere-se à uma revisão sobre o carcinoma de células escamosas de cabeça e pescoço (HNSCC), o qual está envolvido em cerca de 90% dos cânceres de cabeça e pescoço,originado do revestimento escamoso da superfície das mucosas do trato aero digestivo superior,incluindo cavidade oral, faringe, laringe e trato sino nasal. Atualmente, o HNSCC apresenta-se como o sexto tipo de câncer mais comum no mundo, sendo que apenas 50% dos pacientes permanecem vivos por 5 anos, após o diagnóstico. Devido à sua distribuição acelerada e alta prevalência, este tipo de câncer tornou-se, nas últimas décadas, uma das principais ameaças para a saúde pública. Seu desenvolvimento e progressão vem ganhando um destaque especial,considerando-se as novas descobertas relacionadas à instabilidade no cerne da genômica e epigenômica, metabolômica, remodelamento celular e fatores de risco associados, principalmente com o envolvimento de infecções virais e, mais recentemente, aos aspectos imunológicos inerentes ao microambiente tumoral (TME), principalmente o perfil celular (fibroblastos associados ao câncer, linfócitos T reguladores, linfócitos e macrófagos com perfil imunossupressorTh2 e M2, respectivamente e neutrófilos associados ao tumor) e o perfil humoral (quimiocinas, citocinas imunossupressoras tais como TGF-B, IL-13, IL-10, proteínas responsáveis pela quebrada matrix extracelular–metaloproteases e fatores que contribuem para o desenvolvimento e progressão tumoral mediados pela angiogênese, tais como EGF e VEGF). Nos próximos anos, a compreensão da imunobiologia do HNSCC será paralelamente acompanhada de importantes avanços na detecção precoce de pacientes de alto risco, baseada na identificação de biomarcadores,na manipulação do sistema imune e na compreensão da farmacogenômica.

This article refers to a review about head and neck squamous cell carcinoma (HNSCC), which involves about 90% of all head and neck cancers, originated from the squamous lining of the upperaero digestive tract, including the oral cavity, pharynx, larynx and sinonasal tract. Currently, it is known as the 6th most common cancer in the world and only 50% of patients will remain alive for5 years post-diagnosis. Due to its accelerated spreading and its high occurrence, this kind of cancerhas become, in the last decades, one of the major threats to public health. Its development and progression has been gaining special attention, considering the new findings associated to the coreinstability of genetic and epigenetic, metabolomics, cellular remodeling and associated risk factors,especially with the involvement of viral infections and, more recently, to the immunological aspects inherent from the tumor microenvironment (TME) particularly cell profiles (fibroblast associated with cancer, regulatory T cells, lymphocytes, and macrophages with immuno suppressive profile Th2and M2, respectively, and neutrophils associated with tumor) and humoral profile (chemokines, immuno suppressive cytokines such as TGF-B, IL-13, IL-10, proteins responsible for the breakdown of extracellular matrix- metallo proteinase and factors that contribute to the development and tumor progression mediated by angiogenesis, such as EGF and VEGF). In the upcoming years, under standing the immunobiology of head and neck squamous cell carcinoma will be accompanied simultaneous ly by important advances in the early detection of high-risk patients, based on the identification of biomarkers,on the manipulation of the immune system and on the understanding of the pharmacogenomics.

Relationships among the Y balance test, Berg Balance Scale, and lower limb strength in middle-aged and older females

Background: Older females have less dynamic postural control and muscle strength than do middle-aged females. Aging-related strength losses may limit balancing performance. Objective: The purpose of this study was to investigate the ability of the Y Balance Test (YBT) and lower limb strength to discriminate between females in 2 age groups, the relationship between YBT distance and the Berg Balance Scale (BBS), and the degree to which performance on YBT distance is related to lower limb strength in middle-aged and older females. Method: The 40 healthy, independently active females were divided into 2 groups: older and middle-aged. The participants underwent measurements of YBT distance using the YBT, maximal muscular strength of the lower limbs using a handheld dynamometer, and the BBS. Results: The YBT distance in 3 directions and lower limb muscle strength for both lower limbs were significantly lower in the older adults than in the middle-aged group. A moderate correlation but insignificant correlation was found between the YBT composite distance and the BBS score. In the older females, YBT distance was significantly positively correlated with strength of the knee flexor and hip abductor. In the middle-aged group, YBT distance was significantly positively correlated with strength of the knee flexor and hip extensor. Conclusions: Performance on the YBT was influenced by the strength of lower limb. We suggested that YBT can be used to alternative as a measurement of dynamic balance. Proper training programs for older people could include not only strengthening exercises but also YBT performance to improve balance. .

Cancer stem cells - the current status of an old concept: literature review and clinical approaches

As regards their morphology and biology, tumours consist of heterogeneous cell populations. The cancer stem cell (CSC) hypothesis assumes that a tumour is hierarchically organized and not all of the cells are equally capable of generating descendants, similarly to normal tissue. The only cells being able to self-renew and produce a heterogeneous tumour cell population are cancer stem cells. CSCs probably derive from normal stem cells, although progenitor cells may be taken into consideration as the source of cancer stem cells. CSCs reside in the niche defined as the microenvironment formed by stromal cells, vasculature and extracellular matrix. The CSC assays include FACS sorting, xenotransplantation to immunodeficient mice (SCID), incubation with Hoechst 33342 dye, cell culture in non-adherent conditions, cell culture with bromodeoxyuridine. CSCs have certain properties that make them resistant to anticancer therapy, which suggests they may be the target for potential therapeutic strategies.

Rol de las metaloproteinasas y sus inhibidores en patología tumoral / Role of metalloproteinases and their inhibitors in tumors

Las metaloproteinasas (MMPs) intervienen en diversos procesos fisiológicos y patológicos del organismo. Regulan, por ejemplo, las vías de señalización que controlan el crecimiento celular, la inflamación y la angiogénesis. Cumplen funciones moduladoras en el complejo microambiente tumoral interviniendo en las etapas tempranas de la carcinogénesis, en la invasión y la producción de metástasis tumorales. Participan en el procesamiento de moléculas bioactivas como citoquinas, quemoquinas y factores de crecimiento. Las MMPs tienen como substrato a las proteínas de la matriz extracelular (MEC) y su actividad es regulada por inhibidores endógenos (TIMPs). El adecuado balance entre ambas moléculas es fundamental para mantener la homeostasis. Debido al papel que desempeñan en diferentes etapas de la biología del cáncer, son un blanco potencial para futuras estrategias en la terapéutica de esta enfermedad.

Metalloproteinases (MMPs) are involved in different physiological and pathological processes. They regulate several signaling pathways in cell growth, inflammation and angiogenesis. The MMPs modulate the complex tumor microenvironment and are involved in the early stages of carcinogenesis, tumor invasion and metastasic processes. MMPs participate in the processing of bioactive molecules such as cytokines, chemokines and growth factors. Their substrates are the extracellular matrix proteins and endogenous inhibitors (TIMPs) regulate their functions. The accurate balance between these two molecules, MMPs and TIMPs, is critical for maintaining homeostasis. Due to their role in cancer biology, MMPs are potential targets for fu ture therapeutic strategies of this malignant disease.