Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (M.S.)--University of South Florida, 2006. / Title from PDF of title page. Document formatted into pages; contains 58 pages. Includes bibliographical references.

Thesis (Ph. D.)--University of New South Wales, 2007. / Title from caption (viewed on May 7, 2008).

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 5 uppsatser.

Thesis (M.S.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains ix, 98 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 92-98).

Abstract The invasion of a tumour through tissue limiting basement membranes is the critical step in malignant growth. Gelatinases (MMP-2 and MMP-9) are endopeptidases capable of degrading extracellular and pericellular matrix proteins such as collagen IV, the major component of basement membranes. An over-expression of these gelatinases is generally found in malignant tumours and is linked to impaired prognosis in many cancer types. Tissue inhibitors of metalloproteinases (TIMPs), endogenous regulators of the MMP activity, have recently been introduced as multifunctional proteins, which have paradoxical roles in tumour growth. Little data exists on the clinical significance of the gelatinases and TIMPs in gynaecological cancers. In this study the clinical significance of the gelatinases was studied in endometrial and uterine cervical cancers by using immunohistochemical staining with specific antibodies. In epithelial ovarian cancer (EOC) these enzymes and their TIMPs were studied in the preoperative serum samples using ELISA assay. Additionally, sequential serum measurements were performed during chemotherapy to evaluate them as treatment response indicators. In endometrial cancer, MMP-9 positivity correlated to a poor histological differentiation and an advanced clinical stage. High MMP-2 expression correlated to a poor differentiation, and unfavourable survival in stage I cancers, with mortality rates of 5% and 19% in patients with MMP-2 negative versus intensively MMP-2 positive tumours, respectively. In cervical cancers high MMP-2 expression correlated to an increased mortality risk. High MMP-9 expression was connected to a good differentiation of a tumour. In EOC, a high circulating TIMP-1 value correlated to all the examined aggressive features of EOC, including poor survival. The serum measurements of TIMP-1 were uninformative about response evaluation during chemotherapy but paradoxically, an increase in gelatinases and TIMP-2 seemed to reflect a good response to treatment. In conclusion, the data from this study show that high MMP-2 expression in tumour tissue could be prognostic in endometrial and cervical cancer, and preoperative circulating TIMP-1 could serve as an additional prognostic marker in EOC. Studies with larger patient cohorts would be necessary to further explore the value of these enzymes in clinical practice in gynaecological cancers.

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Cancer cell invasion and metastasis is one of the hallmarks of cancer and is frequently the fatal stage in disease progression. One of the key cellular processes underlying invasion and metastasis is cell migration, which is highly dependent on dynamic changes in the actin cytoskeleton. Reactive oxygen species (ROS) are frequently found at elevated levels in cancer and promote disease progression particularly by increasing invasion and metastasis. Although it is known that ROS, specifically H2O2, mediate their downstream effects through the oxidation of proteins on key cysteine residues, very little is known about the direct protein targets of ROS and how the resulting protein oxidation might contribute to cell migration, invasion and metastasis. I have demonstrated that the ROS, H2O2, is produced at increased levels in migrating cells, predominantly at the tips of cell protrusions. Furthermore, I established that protein oxidation is increased in migrating cells and identified the actin binding protein cofilin as one of these oxidised proteins. I have also provided evidence that, when oxidised, cofilin forms oligomers and has a reduced ability to decrease F-actin levels in vitro, which was dependent on cysteine residues 139 and 147. Moreover, I have shown that the oxidation of these cysteine residues is important for directional cell migration and adhesion. Taken together my results provide a direct link between the increased production of ROS at the leading edge of migrating cells and dynamic changes in the actin cytoskeleton that take place in this region to enable cell migration. As the invasion and metastasis of cancer is largely dependent on cell migration, these findings could potentially lead to the development of new ways to target this stage in disease progression.