CCBIO seminar: Karl-Henning Kalland
Heterogeneity and reprogramming plasticity of cancer cells - therapeutic possibilities
Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen
Our research group has established an experimental model consisting of benign prostate cells which were reprogrammed in a stepwise manner to tumorigenic and metastatic cells. Reprogramming of gene expression is essential in tumor progression and represents a difficult challenge for cancer therapy by contributing to cancer cell heterogeneity.
The model was initiated from normal prostate epithelial cells obtained during surgery. Physiological variation of culture conditions and long-term selection gave rise to daughter cells with stepwise acquisition of cancer hallmarks. The cells eventually acquired ability to form tumors and metastases in experimental animals. New cell lines were recovered from the human tumors growing in mice. The new model now consists of a series of cell types which are relatively stable when passaged in sub confluent cultures. Unlimited numbers can therefore be obtained from each cell type. The model has proved useful in a drug discovery program of anticancer leading compounds.
EMT (epithelial to mesenchymal transition) represents an extensive reprogramming of gene expression and is exploited by cancer cells during invasion and spread in the body. EMT has been studied in our experimental model. Cells in epithelial (E) phase differ widely from cells in mesenchymal (M) phase with respect to morphology, functional characteristics, surface markers and activated signal transduction pathways, suggesting that it may be difficult to cure disseminated cancer by attacking only one surface molecule or one signal transduction pathway.
Innovative combination therapies will be needed to treat advanced cancer due to cancer cell heterogeneity. We suggest a strategy of combining immunotherapy with a separate attack on the EMT program in tumor-initiating cell subpopulations. So far, we have identified certain molecular targets that are particularly attractive in our model, including the IL6-STAT3, WNT and AR (androgen receptor) signaling pathways.
Chairperson: Donald Gullberg, CCBIO