Sari Pesonen

Analysis of Epithelial and Mesenchymal Markers in Ovarian Cancer Reveals Phenotypic Heterogeneity and Plasticity

In our studies of ovarian cancer cells we have identified subpopulations of cells that are in a transitory E/M hybrid stage, i.e. cells that simultaneously express epithelial and mesenchymal markers. E/M cells are not homogenous but, in vitro and in vivo, contain subsets that can be distinguished based on a number of phenotypic features, including the subcellular localization of E-cadherin, and the expression levels of Tie2, CD133, and CD44. A cellular subset (E/M-MP) (membrane E-cadherinlow/cytoplasmic E-cadherinhigh/CD133high, CD44high, Tie2low) is highly enriched for tumor-forming cells and displays features which are generally associated with cancer stem cells. Our data suggest that E/M-MP cells are able to differentiate into different lineages under certain conditions, and have the capacity for self-renewal, i.e. to maintain a subset of undifferentiated E/M-MP cells during differentiation. Trans-differentiation of E/M-MP cells into mesenchymal or epithelial cells is associated with a loss of stem cell markers and tumorigenicity. In vivo xenograft tumor growth is driven by E/M-MP cells, which give rise to epithelial ovarian cancer cells. In contrast, in vitro, we found that E/M-MP cells differentiate into mesenchymal cells, in a process that involves pathways associated with an epithelial-to-mesenchymal transition. We also detected phenotypic plasticity that was dependent on external factors such as stress created by starvation or contact with either epithelial or mesenchymal cells in co-cultures. Our study provides a better understanding of the phenotypic complexity of ovarian cancer and has implications for ovarian cancer therapy.

In vivo and in vitro distribution of type 5 and fiber-modified oncolytic adenoviruses in human blood compartments

Abstract Background. Successful tumor targeting of systemically administered oncolytic adenoviruses may be hindered by interactions with blood components. Materials and methods. Blood distribution of oncolytic adenoviruses featuring type 5 adenovirus fiber, 5/3 capsid chimerism, or RGD-4C in the fiber knob was investigated in vitro and in patients with refractory solid tumors. Results. Virus titers and prevalence in serum of patients increased over the first post-treatment week, suggesting replication. Detection of low virus loads was more sensitive in blood clots than in serum, although viral levels > 500 viral particles/mL did not differ significantly between both sample types. While adenovirus bound to erythrocytes, platelets, granulocytes, and peripheral blood mononuclear cells in vitro, the virus was mainly detectable in erythrocytes and granulocytes in cancer patients. Taken together with a temporary post-treatment decrease in thrombocyte counts, platelet activation by adenovirus and subsequent clearance seem likely to occur in humans. Fiber modifications had limited observed effect on virus distribution in blood cell compartments. Neutrophils, monocytes and cytotoxic T lymphocytes were the major leukocyte subpopulations interacting with adenoviruses. Conclusion. Serum and blood clots are relevant to estimate oncolytic adenovirus replication. Insight into viral interactions with blood cells may contribute to the development of new strategies for tumor delivery.

A phase II trial of gefitinib in patients with rising PSA following radical prostatectomy or radiotherapy

Prostate cancer recurrence after therapy with curative intent is often first detected as an increase in prostate-specific antigen (PsA) (“rising PsA syndrome”) which may occur years in advance of clinical recurrence, and may present on opportunity for effective treatment in the context of minimal disease load. Eventually 5–66% of patients with rising PsA receive salvage therapies, the most common of which are radiation of the prostate basin after surgery and hormonal treatments especially in relapses following radical radiotherapy of prostate [1,2]. regrettably, although both modalities are effec-tive in many patients, they also cause significant mor-bidity. Also, radiation is effective only in locally recurrent disease and therefore only 55–72% of rising PsA patients feature PsA response when given salvage radi -ation [3,4]. Hormonal therapies are initially effective in most patients, but they cause numerous long-term side effects and their benefit is often eventually lost, which results in difficult-to-treat castration resistant prostate cancer (CrPC) [5].High expression of epidermal growth factor receptor (