Browsing by Subject "ovarian cancer"

High-grade serous ovarian cancer (HGSOC) is the most common histological type of epithelial ovarian cancer with the five-year survival rate of approximately only 40%. Platinum-based chemotherapy together with surgical cytoreduction is the standard of care in HGSOC. Platinum compounds bind to DNA causing intra- and interstrand cross-links ultimately leading to severe DNA damage in the form of DNA double-strand breaks. Functional DNA repair mechanisms, most importantly homologous recombination (HR), are crucial in repairing these double-strand breaks and maintaining genomic integrity. HR deficiency is found in approximately 50% of HGSOC tumours making these tumours sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors. The androgen receptor (AR) has been reported to be expressed widely in the normal ovarian surface epithelium as well as in malignant ovarian cancer cells. With the current evidence pointing towards the involvement of AR signalling in the maintenance of HR as well as driving radiation resistance, combined or sequential use of anti-androgen therapies together with platinum-based compounds might function as a novel therapeutic approach and lead to the accumulation of DNA damage within HGSOC tumours. Blocking AR signalling in prostate cancer cells receiving androgen deprivation therapy has already been shown to functionally impair HR and result in the upregulation of PARP mediated pathways. To investigate the expression levels of AR within the human primary HGSOC tumour specimens, immunofluorescent immunohistochemistry together with reverse transcriptase polymerase chain reaction were performed. The androgen receptor was found to be expressed in approximately 75% of the patient samples with ≥10% nuclear AR staining. Intriguingly, the AR expression did not differ between primary and metastatic tumours or between chemo-naïve and chemotherapy treated samples. Moreover, the effects of AR inhibition and stimulation on the functional HR capacity of HGSOC cells was examined to elucidate the role of AR signalling in the homologous recombination DNA repair pathway. Receptor manipulation with an antagonist enzalutamide prior to gamma radiation led to a significant decrease in the HR capacity of HR- proficient and AR positive commercial HGSOC cell line OAW28. Furthermore, agonist treatment with dihydrotestosterone increased the HR capacity within these cells. A deeper understanding on the interactions between HR and AR signalling can be utilized in the development of future therapeutic strategies against platinum resistant HGSOC. Pharmaceutically induced HR deficiency has the potential to provide opportunities for a wide range of combination treatment strategies using standard of care chemotherapy in conjunction with molecularly targeted agents towards DNA damage response proteins as well as widen the therapeutic possibilities for the use of PARP inhibitors.

Tiivistelmä Tausta: Nuorena rintasyöpään sairastuneiden lähisukulaisilla tiedetään olevan kohonnut riski sairastua samaan syöpään nuorena. Tutkimuksemme tavoitteena oli selvittää, lisääkö nuoruuden rintasyöpä lähisukulaisten suhteellista riskiä sairastua myös muihin nuoruuden syöpiin kuin rintasyöpään. Tutkimusaineisto ja menetelmät: Arvioimme rintasyöpään alle 41-vuotiaana sairastuneiden naisten alle 41-vuotiaiden sukulaisten suhteellista riskiä sairastua muuhun syöpään kuin rintasyöpään. Tutkimuspopulaatio koostui Suomen Syöpärekisterin väestöpohjaisesta kohortista, joka sisälsi 5 562 rintasyöpäpotilasta sekä potilaiden 54 753 ensimmäisen ja toisen asteen sukulaista. Varhaisen syövän suhteellista riskiä arvioitiin käyttämällä vakioitua ilmaantuvuussuhdetta (SIR), joka kuvaa syövän ilmaantuvuutta suhteessa sukupuolen, iän ja tarkastelujakson osalta vastaavaan väestöön. Tulokset: Havaitsimme tässä tutkimuksessa, että nuorena rintasyöpään sairastuneen lapsilla on muuhun väestöön verrattuna kohonnut riski sairastua varhaiseen syöpään, kun tarkastellaan muita syöpiä kuin rintasyöpää. Lisäksi nuoren rintasyöpäpotilaan sisarusten lapsilla on suurentunut riski sairastua munasarja- sekä kivessyöpään. Varhaisen haimasyövän riski on suurentunut nuorena rintasyöpään sairastuneiden sisaruksilla. Pohdinta: Tulokset osoittavat, että kohonnut varhaisen syövän riski nuoren rintasyöpäpotilaan sukulaisilla ulottuu myös muihin syöpiin kuin rintasyöpään ja ei rajoitu ensimmäisen asteen sukulaisiin. Lisäksi tuloksemme viittaavat siihen, että varhaisella rintasyövällä on jaettuja etiologisia tekijöitä varhaisen kives-, munasarja- sekä haimasyövän kanssa.

High-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer. To date, HGSC has typically been diagnosed late, and the survival rate is poor. Relapses are common despite standardised treatment options, and platinum-based chemotherapy resistance remains frequent. The tumours are generally heterogeneous, which makes HGSC complex. Molecular mechanisms of tumour initiation, progression and chemoresistance are insufficiently understood. Thus, efficacious treatment is challenging, and current options do not help some patients. In addition, a population of cancer cells having stem cell-like properties are suggested to play a role in tumour initiation, progression and chemoresistance. There is an urgent need to better understand prognostic biomarkers and treatment responses in HGSC. With diverse analytical methods, the treatment-unresponsive patients and their outcomes could be identified by predictive biomarkers. This thesis aimed to validate potential tissue biomarkers associated with cancer stem cells and poor prognosis in HGSC, evaluate the usability of the RNAscope technique and briefly review the hypotheses on cancer stem cells. Four putative biomarkers were studied: ALDH1A1, BMI1, MYC and SOX2. The RNAscope technique was used to detect and quantify the biomarker expression. Using diagnostic tumour tissue specimens from 95 patients allowed capturing the expression in situ. With comprehensive clinical information, we could test whether the biomarkers distinguished patients with similar background information but different outcomes. This thesis shows that BMI1 could be a potential prognostic biomarker in high-grade serous carcinoma. The results provide information about the expression patterns of previously identified potential HGSC stemness markers. Proteomics studies such as immunohistochemistry could provide complementary information. When the molecular mechanisms and prognostic markers are better understood, they will provide a promising opportunity to develop novel diagnostic methods for predicting the outcomes and deciding treatments for this complex disease.