Cu toate c\u0103 tratamentul tumorilor non-cerebrale a avansat foarte mult \u00een ultimii ani, terapia metastazelor cerebrale reprezint\u0103 o problem\u0103 nerezolvat\u0103 \u00een practica clinic\u0103. Ca urmare, descoperirea unor noi strategii terapeutice este o sarcin\u0103 primordial\u0103 \u015fi urgent\u0103 a cercet\u0103torilor, \u015fi care depinde de extinderea cuno\u0219tin\u0163elor legate de biologia acestei boli devastatoare. \u00cen urma rezultatelor ob\u0163inute \u00een cadrul implement\u0103rii proiectului UEFISCDI PN-III-P1-1.1-TE-2016-1352, ipoteza noastr\u0103 se bazeaz\u0103 pe faptul c\u0103 interac\u0163iunea pericitelor cu celulele tumorale are o importan\u0163\u0103 deosebit\u0103 \u00een supravie\u0163uirea celulelor metastatice \u00een mediul cerebral. Astfel pericitele reprezint\u0103 o viitoare \u0163int\u0103 terapeutic\u0103 \u00een bolile metastatice ale sistemului nervos central. Folosind modele in vitro \u015fi in vivo, \u015fi utiliz\u00e2nd microscopie avansat\u0103 (cum ar fi superrezolu\u0163ia STED, microscopia cu excita\u0163ie cu doi fotoni \u015fi microscopia de for\u0163\u0103 atomic\u0103), precum \u015fi tehnici de tip screening (analiza secretomului) \u015fi tehnici de validare, vom acumula ample cuno\u015ftin\u0163e asupra rolului pericitelor \u00een formarea metastazelor cerebrale. Vom identifica mecanismele comunica\u0163iei dintre pericite \u015fi celulele de cancer mamar, concentr\u00e2ndu-ne asupra factorilor solubili \u015fi a nanotubilor intercelulari. \u00cen acela\u015fi timp, vom determina rolul pericitelor \u00een vasoconstric\u0163ia indus\u0103 de celulele metastatice \u00een capilarele creierului. Propunem ca \u00een urma implement\u0103rii proiectului s\u0103 ob\u0163inem date \u015ftiin\u0163ifice care pot fi exploatate \u00een viitor \u00een dezvoltarea noilor strategii terapeutice. Ca un rezultat de lung\u0103 durat\u0103 prevedem \u00eembun\u0103t\u0103\u0163irea prognozei bolii metastatice cerebrale.<\/p>\n
Obiectivul principal al proiectului este determinarea mecanismelor prin care pericitele influen\u0163eaz\u0103 pa\u015fii principali ai form\u0103rii metastazelor cerebrale, cum ar fi transmigrarea celulelor tumorale prin peretele capilarelor, formarea ni\u015fei metastatice perivasculare, supravie\u0163uirea \u015fi proliferarea celulelor tumorale \u020bn creier.<\/p>\n
Obiectivele specifice sunt urm\u0103toarele:<\/p>\n
Identificarea factorilor secreta\u0163i de pericite care sunt implica\u0163i \u020bn comunicarea cu celulele metastatice.<\/p>\n
Evaluarea func\u0163iilor specifice ale acestor factori.<\/p>\n
Caracterizerea nanotuburilor membranare formate \u020bntre pericitele cerebrale \u015fi celulele metastatice de carcinom mamar.<\/p>\n
Evaluarea rolului pericitelor \u020bn vasoconstric\u0163ia indus\u0103 de celulele tumorale.<\/p>\n
Vom identifica noi factori secreta\u0163i de pericite care sunt implica\u0163i \u020bn efectele pro-metastatice ale acestor celule, cum ar fi efectul chemoatractiv \u015fi chemoprotector asupra celulelor canceroase, intensificarea adeziunii \u015fi a ratei de proliferare a celulelor tumorale.<\/p>\n
Vom caracteriza rolul nanotuburilor membranare formate \u020bntre pericite \u015fi cululele de carcinom mamar.<\/p>\n
Vom evalua rolul pericitelor \u020bn vasoconstric\u0163ia indus\u0103 de celulele tumorale.<\/p>\n
Despite significant therapeutic advances in non-cerebral malignancies, management of brain metastases is still a significant challenge for clinicians. Therefore, development of new therapeutic strategies is urgently needed, which largely depends on the expansion of our knowledge on the biology of this devastating disease. Based on solid preliminary data obtained during implementation of the UEFISCDI PN-III-P1-1.1-TE-2016-1352 project, we hypothesize that interactions between pericytes and cancer cells have a key role in the survival of metastatic cells in the brain environment and that pericytes represent a future therapeutic target in brain metastatic diseases. Using disease in a dish and in vivo models and applying cutting-edge microscopy (STED superresolution, two-photon and atomic force microscopy), screening (secretome analysis) and validation methods, we will gain important knowledge on the role of pericytes in the formation of brain metastases. We will identify the mechanisms of communication between pericytes and brain metastatic breast cancer cells, including soluble factors and membrane nanotubes. In addition, we will determine the role of pericytes in metastatic extravasation-induced vasoconstriction. We propose that scientific data obtained from completion of the present proposal will lead to identification of mechanisms that could be exploited for future therapeutic strategies, resulting in considerable improvement of the prognosis of brain metastatic disease.<\/p>\n
The main objective of the proposal is to understand the mechanisms through which pericytes influence main steps of brain metastasis formation, including transmigration of tumour cells through brain vessels, formation of the perivascular metastatic niche, survival and proliferation of cancer cells in the brain environment.<\/p>\n
Specific aims are the following:<\/p>\n
To identify brain pericyte-secreted factors involved in communication with metastatic tumour cells.<\/p>\n
To assess the functions of identified pericyte-secreted factors in the metastatic process.<\/p>\n
To characterize membrane nanotube-mediated pericyte-tumour cell interactions.<\/p>\n
To identify pericytes as possible effectors of vasoconstriction in metastatic extravasation.<\/p>\n
We expect to identify new factors involved in the adhesion-enhancing, migration-promoting, chemoprotective and proliferation-supporting effects of pericytes on metastatic cells.<\/p>\n
We expect to characterize the role of tunnelling nanotubes formed between pericytes and metastatic cells.<\/p>\n
We expect to identify pericytes as mediators of tumour cell-induced vasoconstriction and targets of capillary patency restoration.<\/p>\n
<\/p>\n
<\/p>\n","protected":false},"excerpt":{"rendered":"
Abstract Cu toate c\u0103 tratamentul tumorilor non-cerebrale a avansat foarte mult \u00een ultimii ani, terapia metastazelor cerebrale reprezint\u0103 o problem\u0103 nerezolvat\u0103 \u00een practica clinic\u0103. Ca urmare, descoperirea unor noi strategii terapeutice este o sarcin\u0103 primordial\u0103 \u015fi urgent\u0103 a cercet\u0103torilor, \u015fi care depinde de extinderea cuno\u0219tin\u0163elor legate de biologia acestei boli devastatoare. \u00cen urma rezultatelor ob\u0163inute…<\/span><\/p>\n