Title Patogeneza koštanih metastaza solidnih tumora Title (english) Pathogenesis of bone metastasis in solid tumors Author Ivan Vičić Mentor Borislav Belev (mentor)Committee member Damir Vrbanec (predsjednik povjerenstva)Committee member Jasenka Markeljević (član povjerenstva)Committee member Borislav Belev (član povjerenstva)Granter University of Zagreb Defense date and country 2018-07-13, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Abstract Kosti su učestalo mjesto tumorskih metastaza te su češće od primarnih koštanih tumora. Visoka učestalost i velika klinička značajnost postavljaju koštane metastaze visoko na listi prioriteta liječenja tumorskih bolesti. Iako tumorske metastaze mogu zahvatiti bilo koju kost, gotovo isključivo zahvaćaju područja crvene koštane srži. Koncept metastaziranja u kosti jest poremećaj fiziološke koštane pregradnje iskorištavajući iste molekularne mehanizme koje koriste lokalne koštane stanice u regulaciji koštanih metaboličkih procesa. Koštane metastaze mogu se opisati kao osteolitične, osteoblastične i mješovite, iako takve kategorije predstavljaju samo ekstreme kontinuuma poremećaja koštane pregradnje. U osteolitičnim koštanim metastazama, karakterističnim za tumore dojke, diferencijacija i aktivnost osteoklasta je pospješena prvenstveno RANKL/RANK sustavom, i to indirektno, ali i direktno posredovano drugim čimbenicima. Istovremeno je aktivnost osteoblasta inhibirana. Tumorske stanice iskorištavaju čimbenike oslobođene koštanom resorpcijom, uspostavljajući sustav pozitivne povratne sprege koja dalje pospješuje metastatski proces. U osteoblastičnih metastaza, karakterističnih za tumore prostate, čimbenici lučeni iz tumorskih stanica direktno pospješuju diferencijaciju i aktivnost osteoblasta. Osteoklastična aktivnost je također pospješena, doduše u manjoj mjeri, a sustav pozitivne povratne sprege je uspostavljen nešto drugačijim mehanizmom. Tropizam tumorskih stanica je zasebno opisan, a opisani su i mehanizmi vezani uz „uspavanost“ tumorskih stanica i rani razvoj metastaza. Tumorski učinak na koštani mikrookoliš putem izlučenih čimbenika, membranskih čimbenika i egzosoma, je ključni korak u uspostavi početne koštane lezije koja nakon varijabilnog vremena „uspavanosti“ diseminiranih tumorskih stanica napreduje u izraženo stanje. Mnogi mehanizmi su iskorišteni kao terapijske mogućnosti, ili su u kliničkim studijama, no rezultati su raznoliki.
Abstract (english) The bone is a frequent site of tumor metastasis which is more frequently seen than primary bone tumors. High occurrence and significant clinical features impose bone metastasis as a prominent issue in the treatment of a wide variety of tumor diseases. Bone metastasis can involve any bone, but areas of red bone marrow are almost exclusively affected. The basis of metastasizing to the bone is the disruption of the physiological remodeling process by employing the same molecular mechanisms native bone cells use in the lifelong bone turnover. These bone lesions can be characterized as osteolytic, osteoblastic, and mixed, although this classification only represents extremes of a continuum of the bone remodeling dysregulation. In osteolytic bone metastasis, as seen most often in breast cancer, differentiation and function of osteoclasts is promoted via the RANKL/RANK signal pathway indirectly, and other factors independently of that pathway, directly. At the same time osteoblast function is diminished. Tumor cells also take advantage of factors released by bone tissue resorption, thus establishing a vicious cycle that promotes the metastatic process. In osteoblastic metastasis, as seen most often in prostate cancer, the differentiation and function of osteoblasts is promoted by factors secreted from tumor cells directly. Osteoclast activity is also promoted, although to a lesser extent. A positive feedback loop is established by a somewhat different mechanism. Bone osteotropism is separately approached, and mechanisms involved in early stages of bone metastasis and cancer cell dormancy are described. Tumor effect on the bone marrow microenvironment via exosomes, soluble factors, and membrane-bound ligands is of the utmost importance in the establishment of an initial lesion, which, after a variable duration of disseminated tumor cells dormancy, progresses to an overt condition. Many of the described mechanisms are involved in a variety of trials, with a plethora of different results.
Keywords
metastaze solidnih tumora
koštani mikrookoliš u metastatskom procesu
osteolitične metastaze
osteoblastične metastaze
circulus vitiosus u koštanim metastazama
Keywords (english)
solid tumor metastases
bone microenvironment in metastatic process
osteolytic metastases
osteoblastic metastases
vicious cycle in bone metastases
Language croatian URN:NBN urn:nbn:hr:105:563011 Study programme Title: Medicine Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2018-12-21 07:41:52
