Mechanisms of vascularization in murine models of primary and metastatic tumor growth

Directed capillary ingrowth has long been considered synonymous with tumor vascularization. However, the vasculature of primary tumors and metastases is not necessarily formed by endothelial cell sprouting; instead, malignant tumors can acquire blood vessels via alternative vascularization mechanisms, such as intussusceptive microvascular growth, vessel co-option, and glomeruloid angiogenesis. Importantly, in response to anti-angiogenic therapies, malignant tumors can switch from one vascularization mechanism to another. In this article, we briefly review the biological features of these mechanisms and discuss on their significance in medical oncology

Labour power and employment situation in a small rural settlement

Sápon élek születésem óta, ezért kötelességemnek éreztem azt, hogy egy kicsit én is visszaadjak a településnek mindabból, amit az évek során tőle kaptam. Sokan nem is ismerik ezt a kicsiny, kevesebb, mint ezer lelket számláló települést, ezért a dolgozatom egyik célja ez, hogy mindenki, aki ezt a dolgozatot a kezébe veszi, egy kicsit megismerhesse Sápot. A fő téma a munkaerő és foglalkoztatás helyzete, mivel a településnek, mint az ehhez hasonló többi vidéki településeknek is ez az egyik legfőbb problémája. A dolgozatom szakirodalmi részében először Magyarország és a romák munkaerőpiaci helyzetéről fogok beszélni. Mindezek után a dolgozatom további megértéséhez az esszenciális alapfogalmakat fogom letisztázni. A fogalmi áttekintést követően a szakirodalmam második felében a szülőfalumat, Sápot fogom részletesen bemutatni. Célom az, hogy akik eddig talán soha nem is hallottak róla, általam most megismerhessék.BSc/BAGazdasági és vidékfejlesztési agrármérnökiK

International flow of capital through the example of Deutsche Telekom

Dolgozatom két fő részből áll, az első fejezet a nemzetközi tőkeáramlás történetének és tendenciáinak bemutatása napjainkban, valamint Magyarországon. Ebben a részben szerepelnek még a külföldi működőtőkével kapcsolatos fontosabb fogalmak, csoportosítások, elméleti megközelítések. Ismertetem a befektetők motivációit is, valamint a tőkeáramlás előnyeit, hátrányait. A globális vállalatok kapcsán a második fő fejezetben pedig a nemzetközi Deutsche Telekom működését és leányvállalatait mutatom be. Magyarországon két leányvállalattal is rendelkezik, ezek részletesebb bemutatása után következik a piaci pozíció ismertetése. Dolgozatom végén összehasonlítom a 2014 és 2015 II. negyedéves pénzügyi jelentés adatait a Magyar Telekom Csoportot tekintve összesítve, valamint a működési szegmensek eredményeit részletesebben.BSc/BAnemzetközi gazdálkodá

Cell-Free DNA in the Pathogenesis and Therapy of Non-Infectious Inflammations and Tumors

The basic function of the immune system is the protection of the host against infections, along with the preservation of the individual antigenic identity. The process of self-tolerance covers the discrimination between self and foreign antigens, including proteins, nucleic acids, and larger molecules. Consequently, a broken immunological self-tolerance results in the development of autoimmune or autoinflammatory disorders. Immunocompetent cells express pattern-recognition receptors on their cell membrane and cytoplasm. The majority of endogenous DNA is located intracellularly within nuclei and mitochondria. However, extracellular, cell-free DNA (cfDNA) can also be detected in a variety of diseases, such as autoimmune disorders and malignancies, which has sparked interest in using cfDNA as a possible biomarker. In recent years, the widespread use of liquid biopsies and the increasing demand for screening, as well as monitoring disease activity and therapy response, have enabled the revival of cfDNA research. The majority of studies have mainly focused on the function of cfDNA as a biomarker. However, research regarding the immunological consequences of cfDNA, such as its potential immunomodulatory or therapeutic benefits, is still in its infancy. This article discusses the involvement of various DNA-sensing receptors (e.g., absent in melanoma-2; Toll-like receptor 9; cyclic GMP–AMP synthase/activator of interferon genes) in identifying host cfDNA as a potent danger-associated molecular pattern. Furthermore, we aim to summarize the results of the experimental studies that we recently performed and highlight the immunomodulatory capacity of cfDNA, and thus, the potential for possible therapeutic consideration

Origin and Distribution of Connective Tissue and Pericytes Impacting Vascularization in Brain Metastases With Different Growth Patterns

The impact of growth pattern on the distribution of connective tissue and on the vascularization of brain metastases (40 colon, lung and breast carcinoma samples) was analyzed. Most of the cases showed either a "pushing-type" (18/40, mostly colon and lung carcinomas) or a "papillary-type" (19/40, mostly breast carcinomas) growth pattern. There was a striking difference in the growth pattern and vascularization of colon/lung versus breast carcinoma metastases. Pushing-type brain metastases incorporated fewer vessels and accumulated more collagen in the adjacent brain parenchyma, whereas papillary-type brain metastases incorporated more vessels and accumulated collagen in the center of the tumor. We observed duplication of the PDGFRβ-positive pericyte layer accompanied by an increase in the amount of collagen within the vessel walls. The outer layer of pericytes and the collagen was removed from the vessel by invasive activity of the tumors, which occurred either peri- or intratumorally, depending on the growth pattern of the metastasis. Our findings suggest that pericytes are the main source of the connective tissue in brain metastases. Vascularization and connective tissue accumulation of the brain metastases largely depend on the growth pattern of the tumors

Role of (myo)fibroblasts in the development of vascular and connective tissue structure of the C38 colorectal cancer in mice

Abstract Background It remains unclear if the vascular and connective tissue structures of primary and metastatic tumors are intrinsically determined or whether these characteristics are defined by the host tissue. Therefore we examined the microanatomical steps of vasculature and connective tissue development of C38 colon carcinoma in different tissues. Methods Tumors produced in mice at five different locations (the cecal wall, skin, liver, lung, and brain) were analyzed using fluorescent immunohistochemistry, electron microscopy and quantitative real-time polymerase chain reaction. Results We found that in the cecal wall, skin, liver, and lung, resident fibroblasts differentiate into collagenous matrix-producing myofibroblasts at the tumor periphery. These activated fibroblasts together with the produced matrix were incorporated by the tumor. The connective tissue development culminated in the appearance of intratumoral tissue columns (centrally located single microvessels embedded in connective tissue and smooth muscle actin-expressing myofibroblasts surrounded by basement membrane). Conversely, in the brain (which lacks fibroblasts), C38 metastases only induced the development of vascularized desmoplastic tissue columns when the growing tumor reached the fibroblast-containing meninges. Conclusions Our data suggest that the desmoplastic host tissue response is induced by tumor-derived fibrogenic molecules acting on host tissue fibroblasts. We concluded that not only the host tissue characteristics but also the tumor-derived fibrogenic signals determine the vascular and connective tissue structure of tumors

Expansion of Hepatic Stem Cell Compartment Boosts Liver Regeneration.

The hepatic stem cells reside periportally forming the canals of Hering in normal liver. They can be identified by their unique immunophenotype in rat. The oval cells, the progenies of stem cells invade deep the liver parenchyma after activation and differentiate into focally arranged small-and eventually trabecularly ordered regular hepatocytes. We have observed that upon the completion of intense oval cell reactions narrow ductular structures are present in the parenchyma, we propose to call them parenchymal ductules. These parenchymal ductules have the same immunophenotype [cytokeratin (CK)7-/CK19+/alpha-fetoprotein (AFP)-/delta-like protein (DLK)-] as the resting stem cells of the canals of Hering, but different from them reside scattered in the parenchyma. In our present experiments, we have investigated in an in vivo functional assay if the presence of these parenchymal ductules has any impact on a progenitor cell driven regeneration process. Parenchymal ductules were induced either by an established model of oval cell induction consisting of the administration of necrogenic dose of carbontetrachloride to 2-acetaminofluorene pretreated rats (AAF/CCl4) or a large necrogenic dose of diethylnitrosamine (DEN). The oval cells expanded faster and the foci evolved earlier after repeated injury in the livers with preexistent parenchymal ductules. When the animals were left to survive for one more year increased liver tumor formation was observed exclusively in the DEN treated rats. Thus, repeated oval cell reactions are not necessarily carcinogenic. We conclude that the expansion of hepatic stem cell compartment conceptually can be used to facilitate liver regeneration without an increased risk of tumorigenesis

Mechanism of tumour vascularisation in experimental lung metastases

The appearance of lung metastases is associated with poor outcome and the management of patients with secondary pulmonary tumours remains a clinical challenge. We examined the vascularisation process of lung metastasis in six different preclinical models and found that the tumours incorporated the pre-existing alveolar capillaries (i.e. vessel co-option). During the initial phase of vessel co-option, the incorporated capillaries were still sheathed by pneumocytes, but these incorporated vessels subsequently underwent different fates dependent on the model. In five of the models examined (B16, HT1080, HT25, C26 and MAT B-III), the tumour cells gradually stripped the pneumocytes from the vessels. These dissected pneumocytes underwent fragmentation, but the incorporated microvessels survived. In the sixth model (C38), the tumour cells failed to invade the alveolar walls. Instead, they induced the development of vascularised desmoplastic tissue columns. Finally, we examined the process of arterialisation in lung metastases and found that they became arterialized when their diameter grew to exceed 5 mm. In conclusion, our data show that lung metastases can vascularise by co-opting the pulmonary microvasculature. This is likely to have important clinical implications, especially with respect to anti-angiogenic therapies