Title Uloga matriksnih metaloproteinaza u progresiji raka dojke : doktorska disertacija Title (english) Role of matrix metalloproteinases in breast cancer progression Author Dora Fučkar Čupić Mentor Elvira Mustać (mentor)Committee member Elvira Mustać (predsjednik povjerenstva)Granter University of Rijeka Defense date and country 2011-10-07, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Universal decimal classificationUDC ) 616 - Pathology. Clinical medicine Abstract Ciljevi istraživanja: Matriksne metaloproteinaze (MMP), posebno njezina dva člana iz obitelji gelatinaza, MMP-2 i MMP-9, jedini su enzimi sposobni razgraditi fibrilarni kolagen, kao i ostale proteine ekstracelularnog matriksa. Iz brojnih studija poznato je da postoji pojačana ekspresija MMP-2 i MMP-9 u karcinomima dojke, većinom vezana uz nepovoljnu prognozu. Međutim, ima studija s oprečnim rezultatima, koje pojačanu ekspresiju MMP-2 i MMP-9 definiraju kao povoljan faktor u preživljenju
... More bolesnika s karcinomom dojke. Osim toga, pronađeni su dokazi da su ove metaloproteinaze uključene u procese angiogeneze i limfangiogeneze. Stoga su ciljevi ovog istraživanja: utvrditi način ekspresije navedenih metaloproteinaza u karcinomu dojke, na tumorskim i stromalnim stanicama; analizirati ekspresiju MMP-2 i MMP-9 na primarnim nemetastatskim tumorima, zatim primarnim tumorima s metastazama u regionalne limfne čvorove, primarnim tumorima s koštanim metastazama i na lokalnim recidivnim tumorima; ispitati ekspresiju faktora angiogeneze VEGF-A i faktora limfangiogeneze VEGF-C, a potom i gustoću krvnih žila, te limfnih žila; usporediti vrijednosti MMP-2 i MMP-9 s kliničko-patološkim prognostičkim (veličina tumora, histološki i nuklearni gradus, status limfnih čvorova) i prediktivnim faktorima (ekspresija estrogenskih-ER i progesteronskih-PR receptora, HER2 i Ki-67 proliferacijskim indeksom); usporediti vrijednosti MMP-ova s ekspresijom VEGF-A i VEGF–C, te gustoćom krvnih i limfnih žila. Konačni cilj je usporediti ekspresiju navedenih MMP-ova između definiranih skupina bolesnica bez i s navedenim metastazama, odnosno recidivnom bolesti, kao i njihov utjecaj na sveukupno preživljenje. Materijal i metode: U retrospektivnom istraživanju koje je uključilo 76 bolesnica, prikupljeno je ukupno 117 uzoraka tumorskog tkiva karcinoma dojke i izrađeni su tkivni mikroareji, koji su imunohistokemijski obojani na MMP-2, MMP-9, VEGF-A, VEGF-C, CD31 (marker za krvne žile), D2-40 (marker za limfne žile), ER, PR i Ki-67.
Rezultati imunohistokemijske analize matriksnih metaloproteinaza pokazali su da se MMP-2 eksprimira u citoplazmi stromalnih stanica karcinoma dojke, dok se MMP-9 eksprimira u citoplazmi tumorskih stanica.
Usporedbom ekspresije MMP-ova između definiranih skupina, vidjelo se da postoji jača ekspresija MMP-2 u recidivnim tumorima u odnosu na primarne nemetastatske tumore (p=0.001), odnosno da postoji jača ekspresija MMP-9 u skupini primarnih tumora s koštanim metastazama u odnosu na primarne nemetastatske tumore (p=0.045).
Ispitivanjem ekspresije MMP-ova u odnosu na patohistološke karakteristike, statističke analize su potvrdile da postoji pozitivna povezanost MMP-9 i histološkog gradusa (p=0.019), nuklearnog gradusa (p=0.039) i ER pozitiviteta (p=0.039), a negativna s proliferacijskim indeksom (p=0.010).
Ispitivanjem ekspresije MMP-ova i angiogeneze, utvrđeno je da MMP-2 negativno korelira s ekspresijom VEGF-A u skupini primarnih nemetastatskih tumora (p=0.003) i u skupini primarnih tumora s koštanim metastazama (p=0.049), a pozitivno korelira s povećanim brojem limfnih žila u skupini recidivnih tumora (p=0.0001).
Analize preživljenja obzirom na stadij bolesti i ekspresiju MMP-ova, potvrdile su inverznu povezanost stadija i preživljenja bolesnica s MMP-9 pozitivnim tumorima (0.007), odnosno s MMP-2 negativnim tumorima (p=0.010). Analize preživljenja obzirom na metastaze (koštane, odnosno limfogene u aksilarnim limfnim čvorovima) i ekspresiju MMP-ova, pokazale su da je preživljenje značajno kraće u bolesnica s koštanim (p=0.039), odnosno aksilarnim metastazama (p=0.039) čiji su tumori MMP-2 negativni.
Zaključak: Iz rezultata dobivenih statističkom analizom može se zaključiti da je pojačana MMP-2 stromalna ekspresija vjerojatno više udružena s lokalnim invazivnim potencijalom karcinoma dojke, kao i limfangiogenezom, ali ne i s angiogenezom. Za razliku od MMP-2, pojačana ekspresija MMP-9 na tumorskim stanicama više je izražena u primarnim tumorima s koštanim metastazama i ukazuje na progresiju lezije.
Istraživanjem ekspresije matriksnih metaloproteinaza u karcinomima dojke, pokazalo se da je pozitivna ekspresija MMP-9 i negativna ekspresija MMP-2 povezana s lošijim preživljenjem. Less Abstract (english) Objective: Matrix metalloproteinases (MMP), especially their two members from gelatinase family, MMP-2 and MMP-9 are the only enzymes capable of degrading fibrillary collagen and other extracellular matrix proteins. Numerous studies analysed strong and increased MMP-2 and MMP-9 expression in breast cancer and linked it to a poor prognosis. However, there are also studies with opposite results. They defined increased MMP-2 and MMP-9 expression as a good prognostic parameter. There is
... More also evidence that MMPs play a role in angiogenesis and lymphangiogenesis.
Objectives of this study are: to analyse the expression of MMP-2 and MMP-9 in breast cancer, on tumor and stromal cells; to analyse MMP-2 and MMP-9 expression on primary breast cancer without metastases, with nodal metastases, with distant (bone) metastases and on local reccurent tumors; to analyse the expression of angiogenic fakctor VEGF-A and lymphangiogenic factor VEGF-C, and also vascular and lymphatic density; to compare MMP-2 and MMP-9 values to clinico-pathologic prognostic (tumor size, histologic and nuclear grade, lymph node status) and predictive parameters (estrogen-ER and progesteron receptor-PR, HER2 and Ki-67 proliferation index); to compare MMP values to VEGF-A and VEGF-C expression, and also to vascular and lymphatic density. Final objective is to compare the expression of MMP-2 and MMP-9 between defined patients' groups without metastases, with nodal metastases, with bone metastases and on local reccurence, as well as their influence on overall survival. Material and Methods: Tissue microarrays were built from the 117 tumor tissue samples from 76 breast cancer patients in this retrospective study. Immunohistochemistry was performed for MMP-2, MMP-9, VEGF-A, VEGF-C, CD31 (blood vessel marker), D2-40 (lymph vessel marker), ER, PR and Ki-67.
Results of immunohistochemical MMP analysis showed MMP-2 expression on stromal cells of breast cancer, while MMP-9 expressed on tumor cells. Comparing the MMP expression between defined groups, stronger MMP-2 expression was observed in local reccurent tumors than in primary nonmetastatic tumors (p=0.001), and there was significantly stronger MMP-9 expression in primary tumors with bone metastases than in primary nonmetastatic tumors (p=0.045).
Analysing MMP expression and pathohistologic parameters, there was a positive correlation between MMP-9 expression and histological grade (p=0.019), nuclear grade (p=0.039) and ER positivity (p=0.039), and negative correlation between MMP-9 and Ki-67 proliferation index (p=0.010).
Analysing MMP expression and angiogenesis, statistical analysis revealed negative correlation between MMP-2 and VEGF-A in primary nonmetastatic breast cancer (p=0.003) and in primary cancer with bone metastases (p=0.049), and there was positive correlation between MMP-2 and lymph vessel density in reccurent tumors (p=0.0001).
Survival analyses regarding cancer stage confirmed negative correlation between stage and overall survival in patients with MMP-9 positive tumors (p=0.007), as well as with MMP-2 negative tumors (p=0.010). Survival analyses regarding metastases, bone or nodal, showed that there was poor overall survival of patients with MMP-2 negative tumors in group with bone metastases (p=0.039) and nodal metastases (p=0.039).
Conclusion: From statistical analyses, it can be concluded that increased stromal MMP-2 expression is probably more associated with local invasive potential of breast cancer and lymphangiogenesis, but not angiogenesis. Increased MMP-9 expression on tumor cells is seen in tumors with bone metastases and points to a progression of breast cancer.
Exploring the expression of matrix metalloproteinases in breast cancer, statistical analyses indicated association of MMP-9 positivity and MMP-2 negativity with poor survival. Less Keywords
karcinom dojke
MMP-2
MMP-9
angiogeneza
limfangiogeneza
ER
gustoća limfnih žila
metastaziranje
Keywords (english)
breast cancer
MMP-2
MMP-9
angiogenesis
lymphangiogenesis
ER
lymph vascular density
metastases
Language croatian URN:NBN urn:nbn:hr:188:951925 Project Number: 062-0620095-0077 Study programme Title: Biomedicine Postgraduate (doctoral) study programme Catalog URL https://libraries.uniri.hr/cgi-bin/unilib.cgi?form=D1121018047 Type of resource Text Extent 185 str. File origin Born digital Access conditions Open access Terms of use Created on 2017-01-19 19:37:24
