A tumor-indukált lymphangiogenezis mechanizma és gátlásának lehetőségei humán nem-kissejtes tüdőrákban = Tumor induced lymphangiogenesis in human non-small cell lung cancer: pathology and therapeutic implications

A 68916 sz. OTKA-F (pályakezdő, fiatal) pályázati forrás közvetlen felhasználásával befejezett legfontosabb munkánk a Clinical Cancer Research című folyóiratban jelent meg. A 88 kissejtes tüdőrákos (SCLC) és 32 kontroll személyt magába foglaló tanulmányunkban kimutattuk, hogy a kontroll populációhoz képest mind a korai (CD133+/VEGFR3+), mind az érett (CD34+/VEGFR3+) LVEPC-k szignifikánsan nagyobb számban találhatóak a SCLC betegek keringésében. Míg szignifikáns korreláció volt kimutatható az LVEPC szám és a nyirokcsomó (N) státusz között, egyéb klinikopatológiai paraméterekkel (nem, kor, dohányzás, T stádium) az LVEPC szint nem mutatott összefüggést. A daganatellenes kezelések előtti magas LVEPC-szám ugyanakkor szignifikánsan rosszabb prognózissal párosult, felvetve e sejtpopuláció prognosztikus markerként történő alkalmazásának lehetőségét SCLC-s betegek esetében. Bár a „kulcs-lymphangiogén” cytokin VEGF-C szintje a tumoros betegekben magasabb volt, mint az egészséges kontrollokban, a VEGF-C és LVEPC szintek között nem volt kimutatható szignifikáns összefüggés. A fenti tanulmány a vonatkozó irodalomban az első, mely az eddig csak experimentális tumormodellekben vizsgált LVEPC populáció jelenlétét daganatos betegekben is leírja, illetve amely e sejtek klinikai jelentőségét is bizonyítja. A további, részben a jelen OTKA pályázat segítségével befejezett eredeti és „review” közlemények pdf verzióit (melyekben jelen OTKA pályázat száma feltüntetésre került) csatoljuk. | The most important result of the current OTKA grant was published in Clinical Cancer Research in March, 2009. 88 patients with limited stage SCLC (small cell lung cancer) and 32 tumor-free control subjects were included in this study. Peripheral blood (PB) circulating LVEPCs (lymphatic/vascular endothelial progenitor cells) labeled with CD34 and vascular endothelial growth factor receptor-3 (VEGFR-3) antibodies and the serum levels of the key lymphangiogenic molecule VEGF-C were measured by flow cytometry and ELISA, respectively. CD34+/VEGFR3+ LVEPC levels were significantly increased in patients (vs. controls; P<0.01), and there was also significant relationship between LVEPC counts and lymph node metastasis (P<0.01). High pre-treatment circulating LVEPC numbers correlated with poor overall survival (P<0.01). Although we observed significantly elevated VEGF-C concentrations in patients (vs. controls; P<0.01), there was no significant correlation between VEGF-C and LVEPC levels. Moreover, no significant differences in PB VEGF-C levels were seen between patients subgrouped by clinicopathological variables including tumor and lymph node stages and survival. This is the first paper that demonstrates evidence of increased numbers of circulating LVEPCs in patients with a malignant tumor. The pdf versions of additional, related original and review papers are attached

Konzorcium, fő p.: Rosszindulatú daganatok ereződésének mintázata és molekuláris mechanizmusa = Consortional main: Vascularization patterns of cancer and molecular pathways behind

Vizsgálataink során a májáttétek arteriális ereződésére nyertünk bizonyítékokat és új ereződési formáját írtuk le. Pontosítottuk a daganatos intuszuszceptív érsokszorozódás celluláris mechanizmusát. Kisérletes agyi áttétekben az érinkorporációs folyamat részleteit tártuk fel, míg nyirokcsomó áttétekben a vaszkuláris invázió jelenségét igazoltuk. Bemutattuk, hogy a posztnatális vaszkulogenezishez hasonlóan daganatos betegekben a posztnatális limfatikus vaszkulogenezis is reaktiválódik prekurzorok révén, aminek prognosztikai szerepe lehet. Csontáttétes veserákokban a HIF-jelpálya EGFR-kapcsolt sajátosságait figyeltük meg. Bemutattuk, hogy az in vivo EPO kezelés képes csökkenteni kisérleti daganat HIF-jelpályájának aktivitását. Kimutattuk hogy a HIF-inaktiváló ZnSO4 kezelésnek jelentős progressziófékező hatása van melanoma modellben. Igazoltuk, hogy daganatokban az apelin új angiogén citokin. Adatokat szolgáltattunk arra hogy vastagbélrákok anti-VEGF kezelésének hatásossága a daganat K-RAS státuszától független. Bemutattuk hogy anti-VEGF kezelés EPO-val történő kombinálása hatékonyan csökkenti kisérleti daganat vérellátását. Kimutattuk, hogy VEGFR gátló kezelés hatására kisérleti daganatokban a VEGFR-független intuszuszceptív érsokszorozódás aktiválódik. | We have provided evidences for the arterial blood supply of liver metastases and defined novel vascularization forms. Studies identified details of the cellular mechanism involved in intususceptive angiogenesis of experimental tumors. We have defined details of the vessel incorporation of experimental brain metastases and provided first evidences for the existence of vascular invasion in lymph node metastases. Studies identified for the first time, that similar to postnatal vasculogenesis, lymphatic vasculogenesis is also reactivated by specific precurzors in cancer patients which might have prognostic significance. We have found in bone-metastatic renal cell cancer the further activation of the HIF-pathway associated with EGFR. We provided the first evidence that EPO administration in vivo inhibits activation of the HIF-pathway in experimental tumors. In experimental melanoma model we found that the HIF-inactivating ZnSO4 treatment has significant anti-metastatic effect. For the first time, our studies provided evidence for apelin as cancer angiogen. Clinical studies provided data on the RAS-status independent efficacy of anti-VEGF therapy of colorectal cancer. On the other hand, we have shown that combination of anti-VEGF therapy with EPO administration efficiently decreases perfusion of experimental tumors. Finaly, we have also shown that VEGFR inhibitor therapy of experimental cancer activates the VEGFR-independent intususceptive angiogenesis

Suicide in Hungary-epidemiological and clinical perspectives

Annual suicide rates of Hungary were unexpectedly high in the previous century. In our narrative review, we try to depict, with presentation of the raw data, the main descriptive epidemiological features of the Hungarian suicide scene of the past decades. Accordingly, we present the annual suicide rates of the period mentioned and also data on how they varied by gender, age, urban vs. rural living, seasons, marital status, etc. Furthermore, the overview of trends of other factors that may have influenced suicidal behavior (e.g., alcohol and tobacco consumption, antidepressant prescription, unemployment rate) in the past decades is appended as well. Based on raw data and also on results of the relevant papers of Hungarian suicidology we tried to explain the observable trends of the Hungarian suicide rate. Eventually, we discuss the results, the possibilities, and the future tasks of suicide prevention in Hungary

Circulating endothelial cells, bone marrow-derived endothelial progenitor cells and proangiogenic haematopoietic cells in cancer: From biology to therapy

Vascularization, a hallmark of tumorigenesis, is classically thought to occur exclusively through angiogenesis (i.e. endothelial sprouting). However, there is a growing body of evidence that endothelial progenitor cells (EPCs) and proangiogenic hematopoietic cells (HCs) are able to support the vascularization of tumors and may therefore play a synergistic role with angiogenesis. An additional cell type being studied in the field of tumor vascularization is the circulating endothelial cell (CEC), whose presence in elevated numbers reflects vascular injury. Levels of EPCs and CECs are reported to correlate with tumor stage and have been evaluated as biomarkers of the efficacy of anticancer/antiangiogenic treatments. Furthermore, because EPCs and subtypes of proangiogenic HCs are actively participating in capillary growth, these cells are attractive potential vehicles for delivering therapeutic molecules. The current paper provides an update on the biology of CECs, EPCs and proangiogenic HCs, and explores the utility of these cell populations for clinical oncology

Current therapy of KRAS-mutant lung cancer

KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Of note, KRAS-related studies that included general non-small cell lung cancer (NSCLC) population instead of LADC patients should be very carefully evaluated. Recently, however, comprehensive genomic profiling and wide-spectrum analysis of other co-occurring genetic alterations have identified unique therapeutic vulnerabilities. Novel targeted agents such as the covalent KRAS G12C inhibitors or the recently proposed combinatory approaches are some examples which may allow a tailored treatment for LADC patients harboring KRAS mutations. This review summarizes the current knowledge about the therapeutic approaches of KRAS-mutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications

FGF2 and EGF induce epithelial-mesenchymal transition in malignant pleural mesothelioma cells via a MAPKinase/MMP1 signal

Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial-mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGF beta or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma

Szemelvények a Semmelweis Egyetem, az Országos Onkológiai Intézet és az Országos Korányi Tbc és Pulmonológiai Intézet együttműködésén alapuló tüdőrák-kutatási programból

Lung cancer places a significant socio-economic burden on the Hungarian population. This overview summarizes the findings of collaborative translational lung cancer research efforts of three Hungarian flagship academic institutions, the Semmelweis University, the National Institute of Oncology and the National Koranyi Institute of TB and Pulmonology. With regards to the molecular factors regulating tumor angiogenesis, we identified the prognostic significance of apelin and erythropoietin receptor (EPOR) expression in non-small cell lung cancer (NSCLC). Furthermore, the impact of KRAS mutation subtypes and ERCC1 (excision repair cross-complementation group 1) expression on the response to platinum-based chemotherapy have been studied. We also described the epidemiology and predictive power of rare EGFR (epidermal growth factor receptor) mutations in a large Hungarian patient cohort. Lastly, the expression of molecular factors associated with NSCLC progression was studied specifically in brain metastatic matched cases series. These preclinical and clinical studies provide clinically relevant information that hopefully will contribute to the improvement of lung cancer patient care

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

The plasma membrane Ca2+ pump PMCA4b inhibits the migratory and metastatic activity of BRAF mutant melanoma cells

Oncogenic mutations of BRAF lead to constitutive ERK activity that supports melanoma cell growth and survival. While Ca2+ signaling is a well-known regulator of tumor progression, the crosstalk between Ca2+ signaling and the Ras-BRAF-MEK-ERK pathway is much less explored. Here we show that in BRAF mutant melanoma cells the abundance of the plasma membrane Ca2+ ATPase isoform 4b (PMCA4b, ATP2B4) is low at baseline but markedly elevated by treatment with the mutant BRAF specific inhibitor vemurafenib. In line with these findings gene expression microarray data also shows decreased PMCA4b expression in cutaneous melanoma when compared to benign nevi. The MEK inhibitor selumetinib-similarly to that of the BRAF-specific inhibitor-also increases PMCA4b levels in both BRAF and NRAS mutant melanoma cells suggesting that the MAPK pathway is involved in the regulation of PMCA4b expression. The increased abundance of PMCA4b in the plasma membrane enhances [Ca2+ ]i clearance from cells after Ca2+ entry. Moreover we show that both vemurafenib treatment and PMCA4b overexpression induce marked inhibition of migration of BRAF mutant melanoma cells. Importantly, reduced migration of PMCA4b expressing BRAF mutant cells is associated with a marked decrease in their metastatic potential in vivo. Taken together, our data reveal an important crosstalk between Ca2+ signaling and the MAPK pathway through the regulation of PMCA4b expression and suggest that PMCA4b is a previously unrecognized metastasis suppressor