Role Of Microenvironmental Factors Research Articles

The role of microenvironmental factors in the pre-ovulatory oocyte in the pathogenesis of “poor” ovarian response to in vitro fertilization (IVF) programs

Background. The “poor” response to ovarian stimulation during IVF (in vitro fertilization) cycles depends on various factors, including the biochemical composition of the follicle microenvironment. Recent studies have focused on the relationship between vascular tone regulators, angiogenic factors, oxidative stress, and the quality of oocytes. Despite this, there is still no consensus on the exact effect of these factors on folliculogenesis or their role in “poor” responses.Objective. To evaluate the content of biochemical factors and regulators of vascular tone and angiogenesis in follicular fluid in patients with a “poor” ovarian response to stimulation in IVF programs, compared to similar indicators in women with a normal ovarian response.Materials and methods. An open prospective cohort study was conducted, including 56 patients who were part of the IVF program. The criterion for separating the cohort of women was their response to controlled ovarian stimulation during the IVF cycle. Women with a “poor” response (n=32) were placed in the main group, while those with a normal response (n=24) were in the comparison group. Follicular fluid samples from women with a “poor” response were divided into two subgroups based on the presence or absence of an oocyte-cumulus complex in the follicle. The biochemical and soluble regulatory factors in follicular fluid were analyzed in both groups after controlled ovarian stimulation was completed. Statistical analysis of the data was done using methods from variation statistics. A critical level of significance for the differences was set at p ≤0.05.Result. The levels of urea, glucose, high-density lipoprotein, and total antioxidant status (TAOS) in follicular fluid (FF) from patients with a “poor” ovarian response were statistically significantly higher compared to those in the control group. The levels of bilirubin, low-density lipoprotein, and uric acid were also significantly lower in VF from patients in the main group compared to the control group, p<0.05. The indices of vascular endothelial growth factor (VEGF-A) and vascular endothelial growth receptor-2 (VEGFR-2) in FF from women with a “poor” response were significantly lower than those from patients with a normal response, while the levels of endogenous nitric oxide were significantly higher in the former group compared to the latter, p<0.05.Conclusion. The absence of an oocyte-cumulus complex in the pre-ovulatory follicle, which is associated with a “poor” response of the ovary to stimulation, is likely due to a disruption in vascularization processes. This is supported by a decrease in the levels of pro- and anti-angiogenic factors, such as VEGF-A and VEGFR-2.

Age-related differences in the bone marrow stem cell niche generate specialized microenvironments for the distinct regulation of normal hematopoietic and leukemia stem cells

The bone marrow (BM) microenvironment serves as a stem cell niche regulating the in vivo cell fate of normal hematopoietic stem cells (HSC) as well as leukemia stem cells (LSCs). Accumulating studies have indicated that the regeneration of normal HSCs and the process of leukemogenesis change with advancing age. However, the role of microenvironmental factors in these age-related effects are unclear. Here, we compared the stem cell niche in neonatal and adult BM to investigate potential differences in their microenvironmental regulation of both normal and leukemic stem cells. We found that the mesenchymal niche in neonatal BM, compared to adult BM, was characterized by a higher frequency of primitive subsets of mesenchymal stroma expressing both platelet-derived growth factor receptor and Sca-1, and higher expression levels of the niche cross-talk molecules, Jagged-1 and CXCL-12. Accordingly, normal HSCs transplanted into neonatal mice exhibited higher levels of regeneration in BM, with no difference in homing efficiency or splenic engraftment compared to adult BM. In contrast, in vivo self-renewal of LSCs was higher in adult BM than in neonatal BM, with increased frequencies of leukemia-initiating cells as well as higher lympho-myeloid differentiation potential towards biphenotypic leukemic cells. These differences in LSC self-renewal capacity between neonates and adults was abrogated by switching of recipients, confirming their microenvironmental origin. Our study provides insight into the differences in leukemic diseases observed in childhood and adults, and is important for interpretation of many transplantation studies involving neonatal animal models.

Abstract 799: Tumour micro-environmental factors and the development of mammary calcifications: Recent findings from an in-vitro model

Abstract The presence of microcalcifications on mammographic images represents a highly valuable tool in the early detection of breast cancer, often allowing radiographers to diagnose mammary tumours at an early, in-situ stage. The presence of microcalcifications has also been linked to a number of unfavourable prognostic factors including decreased survival and an increased probability of relapse. Despite their long history of use in the clinic, the precise mechanisms by which microcalcifications are formed remains poorly understood. Pathological soft-tissue calcification is often considered the result of an imbalance between pro- and anti-calcifying factors. However, the possible impact of such an imbalance has not been studied in the context of breast calcification. We have established an in-vitro model of microcalcification formation using the triple-negative adenocarcinoma cell line MDA-MB-231. When cultured in the presence of the osteogenesis-promoting reagents β-glycerophosphate, ascorbic acid and dexamethasone, calcified deposits begin to form by Day 14, as verified by Alizarin Red staining and the quantitative o-cresolphthalein assay. Following the establishment of our model, we set out to identify the underlying molecular triggers initiating the calcification process, in particular the role of micro-environmental factors. Altered magnesium homeostasis has been suggested as an important mediator of tissue calcification. We found that a slight increase in magnesium concentration almost completely blocked calcium deposition in our model. Previous studies in other tissues have shown this protective effect to be dependent on the cation channel TRPM7 which is increased in breast cancer patients with calcifications compared to those without. Unexpectedly, inhibition of the TRPM7 channel by two separate compounds (2-APB and NS-8593) not only failed to reverse the inhibition of microcalcification formation by exogenous magnesium, but actually further decreased calcium deposition by Day 28, suggesting that calcium influx via the TRPM7 channel may be promoting development of mammary calcifications. Finally, we investigated the effect of several tumour associated cytokines on the rate of calcium deposition and found that IL-1β and TNF-α blocked mineralisation whilst IL-6 and BMP2 lead to an increase. Interestingly, co-administration of IL-6 alongside a soluble form of its receptor (sIL-6R) was observed to promote mineralisation even in the absence of dexamethasone, which had previously been essential to the formation of calcifications in our model. To date, our model has yielded a number of important insights into the formation of calcifications in breast cell lines, many of which recapitulate observations from patient studies. It is hoped that this work will contribute to our understanding of the origin of these pre-invasive diagnostic clues. Citation Format: Shane O'Grady, Maria P. Morgan. Tumour micro-environmental factors and the development of mammary calcifications: Recent findings from an in-vitro model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 799. doi:10.1158/1538-7445.AM2017-799

Hypoxia-inducible factor (HIF) network: insights from mathematical models

Oxygen is a crucial molecule for cellular function. When oxygen demand exceeds supply, the oxygen sensing pathway centred on the hypoxia inducible factor (HIF) is switched on and promotes adaptation to hypoxia by up-regulating genes involved in angiogenesis, erythropoiesis and glycolysis. The regulation of HIF is tightly modulated through intricate regulatory mechanisms. Notably, its protein stability is controlled by the oxygen sensing prolyl hydroxylase domain (PHD) enzymes and its transcriptional activity is controlled by the asparaginyl hydroxylase FIH (factor inhibiting HIF-1).To probe the complexity of hypoxia-induced HIF signalling, efforts in mathematical modelling of the pathway have been underway for around a decade. In this paper, we review the existing mathematical models developed to describe and explain specific behaviours of the HIF pathway and how they have contributed new insights into our understanding of the network. Topics for modelling included the switch-like response to decreased oxygen gradient, the role of micro environmental factors, the regulation by FIH and the temporal dynamics of the HIF response. We will also discuss the technical aspects, extent and limitations of these models. Recently, HIF pathway has been implicated in other disease contexts such as hypoxic inflammation and cancer through crosstalking with pathways like NFκB and mTOR. We will examine how future mathematical modelling and simulation of interlinked networks can aid in understanding HIF behaviour in complex pathophysiological situations. Ultimately this would allow the identification of new pharmacological targets in different disease settings.

Liana diversity and abundance as related to microenvironment in three forest types located in different elevational ranges of the Eastern Himalayas

Background: Liana diversity and abundance in forests along an elevational range is poorly understood. Aims: To study the diversity and abundance of lianas in three forest types located in different elevational belts of the Eastern Himalayas, and to explore the role of microenvironmental factors in relation to liana abundance. Methods: Adult (≥ 0.2cm diameter at breast height) and juvenile lianas were enumerated in 0.1ha and 1m2 plots in lower montane, montane and upper montane forests between 1200 and 3000m above sea level. Ten microenvironmental variables were related to liana density within each forest type using stepwise forward multiple regression analysis, and across the forest types by using Canonical Correspondence Analysis (CCA). Results: Liana species richness followed the order: lower montane > montane > upper montane forest. Light and soil phosphorus (P) concentration were related to adult liana density. Soil pH, P, light and relative humidity were related to seedling density. The positioning of 43 liana species with respect to light, soil pH, nitrogen and P gradients in CCA plots indicated species-specific microenvironmental preferences. Conclusions : Liana diversity and abundance decreased with increasing elevation, and at each elevation were related to specific microenvironmental variables and differential species response.

STAT3 as a molecular target in pediatric T-cell leukemia.

9564 Background: Increasing evidence suggest an important role for microenvironmental factors in the biology of pediatric acute leukemias. However, little is known on how oncogenic events and micro...

Molecular pathways in follicular lymphoma

Follicular lymphoma (FL) is one of the most common B-cell non-Hodgkin's lymphomas. The initiating genetic event found in approximately 90% of FL is the t(14;18), causing constitutive expression of the antiapoptotic BCL-2 protein. The exact secondary alterations leading to full FL development are still poorly defined. In this review, we address (i) the genetic pathways associated with tumorigenesis and progression of FL, (ii) the role of micro-environmental factors with emphasis on B-cell receptor ligands and (iii) lymphoma models in mice and what they teach us about lymphomagenesis in man.