Title ULOGA OSTEOPONTINA U PROGRESIJI NESITNOSTANIČNOG RAKA PLUĆA
Title (english) THE ROLE OF OSTEOPONTIN IN NON-SMALL CELL LUNG CANCER PROGRESSION
Author Christophe Štemberger MBZ: 44040788759
Mentor Ksenija Jurinović (mentor)
Committee member Ljiljana Bulat-Kardum (predsjednik povjerenstva)
Committee member Sven Seiwerth (član povjerenstva)
Committee member Maja Krašević (član povjerenstva)
Committee member Ksenija Jurinović (član povjerenstva)
Granter University of Rijeka Faculty of Medicine (Department of General Pathology and Pathological Anatomy) Rijeka
Defense date and country 2016-03-02, Croatia
Scientific / art field, discipline and subdiscipline BIOMEDICINE AND HEALTHCARE Clinical Medical Sciences Pathology
Universal decimal classification (UDC ) 61 - Medical sciences
Abstract Cilj: Osteopontin je multifunkcionalna proteinska molekula koja ima važnu ulogu u nastanku
i progresiji malignih tumora. Svoje djelovanje ostvaruje preko integrinskih i neintegrinskih
receptora (molekula CD44v6), te djeluje na procese proliferacije, apoptoze, angiogeneze,
invazije i metastaziranja tumora. Cilj ovog istraživanja bio je istražiti ekspresiju osteopontina
u normalnom tkivu pluća, te u tumorskom tkivu nesitnostaničnog raka pluća (NSSRP) i
njegovih osnovnih histoloških podtipova, ispitati odnos osteopontina prema kliničkopatološkim parametrima poput veličine tumora, stupnja diferencijacije, statusa limfnih
čvorova, pT, TNM i petogodišnjeg preživljenja, ispitati odnos osteopontina prema
receptorskim molekulama u tumorskim stanicama, te procijeniti utjecaj osteopontina na
apoptozu i proliferaciju tumorskih stanica.
Ispitanici i metode: Ekspresija osteopontina i njegovih receptorskih molekula, kao i
proliferativna aktivnost tumorskih stanica (Ki67) istražena je imunohistokemijskom
metodom na uzorku izgrađenih tkivnih mikroregija iz točno određenih regija (centralne
tumorske regije, invazivna fronta i tkivo metastaze) 110 NSSRP-a, dok je apoptotička
aktivnost stanica određena TUNEL metodom. Ekspresija osteopontina uspoređena je sa
kliničko-patološkim parametrima, ekspresijom αv-integrina i molekule CD44v6, te sa
indeksom proliferacije i apoptoze.
Rezultati: Ekspresija osteopontina i receptorskih molekula u tumorskom tkivu je jača nego u
normalnom tkivu pluća. U skupini NSSRP-a jača je ekspresija osteopontina u
adenokarcinomima (p<0.001), a ekspresija αv-integrina (p<0.001) i molekule CD44v6
(p<0.001) je jača u karcinomima pločastih stanica. Nije primjećena značajna korelacija
ekspresije osteopontina i promatranih kliničkopatoloških parametara. Ekspresija
IV
osteopontina je jača u invazivnoj fronti adenokarcinoma (p=0.041) i karcinoma pločastih
stanica (p=0.011) u odnosu na centralne regije, te u metastatskom tkivu NSSRP-a (p=0.042) u
odnosu na primarni tumor. Utvrđena je jača ekspresija osteopontina u bolje diferenciranim
tumorskim regijama NSSRP-a (p=0.006), te jača ekspresija αv-integrina (p=0.038) i molekule
CD44v6 (p=0.001) u područjima lošije diferencijacije adenokarcinoma, kao i jača ekspresija
molekule CD44v6 u bolje diferenciranim regijama karcinoma pločastih stanica (p=0.011).
Apoptotička aktivnost se između histoloških podtipova nije značajno razlikovala (p=0.455),
dok je proliferativna aktivnost bila viša u karcinomu pločastih stanica (p<0.001). Ekspresija
osteopontina u adenokarcinomima je povezana uz niski indeks apoptoze (p=0.006) što
upućuje na antiapoptotičku ulogu osteopontina u adenokarcinomima. Utvrđena je pozitivna
korelacija ekspresije osteopontina i αv-integrina u adenokarcinomima početnog TNM stadija
(p=0.033), kao i snažna pozitivna korelacija ekspresije obje receptorske molekule u
skupinama NSSRP-a (p<0.001) i karcinoma pločastih stanica (p=0.008). Kod adenokarcinoma
je istovremena koekspresija osteopontina i αv-integrina povezana sa niskim apoptotičkim
indeksom (p<0.01). Pozitivni status limfnih čvorova i inicijalni TNM stadij NSSRP-a udruženi
su sa kraćim preživljenjem.
Zaključak: Pojačana ekspresija osteopontina je u adenokarcinomu pluća povezana sa niskim
apoptotičkim indeksom, vjerojatno preko αv-integrinskog receptorskog kompleksa, te na taj
način promovira preživljenje tumorske stanice. Jača ekspresija osteopontina u invazivnoj
fronti tumora i u metastazi sugerira njegovu ulogu u progresiji i metastaziranju NSSRP-a.
Abstract (english) Objectives: Osteopontin is a multifunctional protein molecule that plays an important role in
the development and progression of malignant tumors. Its action is achieved via integrin
receptor molecules or the non-integrin receptor (CD44v6), and acts on the processes of
proliferation, apoptosis, angiogenesis, invasion and metastasis.
The aim of this study was to investigate the expression of osteopontin in normal lung tissue,
in tumor tissue non-small cell lung cancer (NSCLC) and its major histologic subtypes, to
examine the relationship of osteopontin to clinicopathological parameters such as tumor
size, degree of differentiation, lymph node status, pT, TNM and five-year survival, to
examine the relationship of osteopontin and its receptor molecules in the tumor cells, and
to assess the possible effect of osteopontin on apoptosis and the proliferation of tumor cells.
Patients and Methods: The expression of osteopontin and its receptor molecules, as well as
the proliferative activity of tumor cells (Ki67) was investigated by an immunohistochemical
method using tissue microarrays from precise tumor regions (central tumor tissue, invasive
front and metastatic tissue) of 110 NSCLC, while the apoptotic activity of the cells was
determined by the TUNEL method. Osteopontin expression was compared to the
clinicopathological parameters, expression of αv-integrins and CD44v6 molecule, and the
proliferation index and apoptosis index.
Results: Expression of osteopontin and its receptor molecules in the tumor tissue is stronger
than in the normal lung tissue. In the NSCLC group, osteopontin expression was stronger in
adenocarcinomas (p <0.001), and the expression of αv-integrins (p <0.001) and molecules
CD44v6 (p <0.001) was stronger in squamous cell carcinoma. No significant correlation was
noticed between the expression of osteopontin and clinicopathological parameters.
VI
Osteopontin expression was stronger in invasive front of adenocarcinoma (p = 0.041) and
squamous cell carcinoma (p = 0.011) compared to the central tumor region, and in
metastatic tissue of NSCLC group (p = 0.042) compared to the primary tumor. We observed
highly expressed osteopontin in well differentiated tumor regions of NSCLC (p=0.006), higher
αv-integrin (p=0.038) and CD44v6 (p=0.001) expression in the areas of lower differentiated
adenocarcinoma, and highly expressed molecule CD44v6 in well differentiated areas of
squamous cell carcinoma (p=0.011). Among the histological subtypes apoptotic activity was
not significantly different (p=0.455), whereas the proliferative activity was higher in
squamous cell carcinoma (p<0.001). Expression of osteopontin in adenocarcinomas is
associated with a low index of apoptosis (p = 0.006) suggesting an antiapoptotic role of
osteopontin. A positive correlation between expressions of osteopontin and αv-integrin in
initial lung adenocarcinomas stage was found (p=0.033), as well as strong positive
correlation of expressions of the two receptor molecules in a NSCLC group (p<0.001) and
squamous cell carcinomas group (p=0.008), when the simultaneous co-expression of
osteopontin and αv-integrin correlated with low apoptotic index (p <0.01). The positive
lymph node status and higher TNM stage are associated with shorter survival.
Conclusion: In adenocarcinoma, osteopontin overexpression is associated with low
apoptotic index, probably through the activation of an αv-integrin receptor molecule. As a
result, osteopontin promotes the survival of tumor cells. A stronger expression of
osteopontin in the invasive front of the tumor and metastasis suggests a role in the
progression and metastasis of NSCLC.
Keywords
Analiza tkivnih mikroregija
Apoptoza
αv-integrin
CD44v6
Imunohistokemija
Osteopontin
Rak pluća
Keywords (english)
Apoptosis
αv-integrin
CD44v6
Immunohistochemistry
Lung cancer
Osteopontin
Tissue array analysis
Language croatian
URN:NBN urn:nbn:hr:184:302182
Project Number: 062-0620095-0078 Title: Uloga osteopontina u progresiji tumora Title: The role of osteopontin in tumor progression Leader: Ksenija Lučin Jurisdiction: Croatia Funder: MZOS Funding stream: ZP
Study programme Title: Biomedicine Postgraduate (doctoral) study programme Study programme type: university Study level: postgraduate Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
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Created on 2022-03-18 15:51:43