The Extracellular Matrix of Ovarian Cancer

Overview

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Ovarian cancer is an insidious disease that typically afflicts women in their latter years. With an aging population, the number of women with ovarian cancer is expected to rise in Australia. On average, three women are diagnosed with ovarian cancer daily, and two die of the disease. Ovarian cancer is the seventh most common cause of death in Australian women with a survival rate only half that for women with breast cancer. Ovarian cancer is particularly deadly because symptoms are not very specific, and no screening test is available.  Consequently it is often detected at an advanced stage with a poor prognosis for the patient and is the leading cause of death and reduced quality of life of all gynaecological cancers. Clearly improvement is needed in both the early detection and treatment of ovarian cancer. The extracellular matrix (ECM) forms a protein support for cells and tissues.  ECM is a complex arrangement of macromolecules that is produced locally and has distinct tissue expression patterns.  The binding of specific growth factors further enhances the functionality of the ECM.  The composition of ECM is regulated both by its synthesis, and by its degradation by proteases, including matrix metalloproteases (MMP) and kallikreins (KLK).  The interaction between cells and ECM occurs via transmembrane proteins called integrins.  ECM-cell interactions affect cellular adhesion, migration and invasiveness.  The ability of cells to survive detachment is a feature of tumour cells, and specific ECM molecules such as laminin and collagen type IV have been shown to improve the survival of cells in 3D culture.  Laminin 332 is expressed in a variety of cancers and in the ovary is localised to the basal lamina underlying the ovarian surface epithelium.  Laminin 332 has been shown to be important for the growth and metastasis of tumour cells in vivo and there is increased expression of laminin 332 and MMP7 in early metastasis in lung.  This evidence suggests that the expression of specific ECM proteins is important in the pathophysiology of metastasis.  In addition, ECM may affect the bio-diffusion of drugs and may be an important factor in the efficacy of drug cancer treatments.  Furthermore, high levels of KLK proteases are related to short survival time and chemoresistance in epithelial ovarian cancer (EOC) patients.  Using a unique model that mimics a critical stage in progression of ovarian cancer, this project aims to identify the composition of the protein scaffold supporting tumour cells, and determine its role in the survival of these cells following treatment with chemotherapeutic drugs.

We hypothesis that the composition of ECM will differ between primary and metastatic EOC tumours, and will have a role in the metastasis of EOC.

We aim to:

  1. Characterise the expression of ECM molecules produced by SKOV3 cells in conditions that mimic the in vivo 3D condition (3D culture), in comparison to conventional 2D culture.
  2. Characterise the expression of ECM molecules produced by patient ascetic EOC cells.
  3. Identify differentially expressed integrins in 2D and 3D culture of SKOV3 cells.
  4. Determine if the in vitro expression ECM is altered by over-expression of the proteases KLK4/KLK7.

Approaches

  1. Cell culture: 2D monlayer, 3D-suspension and 3D-matrices and chemosensitivity assays.
  2. RT_PCR, microarray, Western immunoblot, immunohistochemistry and microscopy.

Further comments:

Ovarian cancer is the seventh most common cause of death in Australian women, with a survival rate half that for women with breast cancer.  Ovarian cancer is particularly deadly because symptoms are not very specific, and no screening test is available.  Consequently it is often detected at an advanced stage with a poor patient prognosis.  Improvement is needed in both the early detection and treatment of ovarian cancer, consequently we need a better understanding of the behaviours of ovarian cancer cells in order to develop better therapeutic strategies.  The extracellular matrix (ECM) forms a protein support for cells and tissues.  ECM is a complex arrangement of macromolecules that is produced locally and has distinct tissue expression patterns.  The binding of specific growth factors further enhances the functionality of the ECM.  The composition of ECM is regulated both by its synthesis and its degradation.  ECM-cell interactions affect cellular adhesion, migration and invasiveness.  Specific ECM has been shown to improve the survival of cells in culture and be important for cancer spread.  We aim to identify the composition of the protein scaffold supporting ovarian tumour cells, and determine its role in the survival of these cells following treatment with chemotherapeutic drugs.

Study level
PhD, Masters, Honours
Supervisors
QUT
Organisational unit

Science and Engineering Faculty

Research area

Cell and Molecular Biosciences

Contact
Please contact the supervisors.