Cancer Stem Cells
It must be said that these numbers are the overall numbers for all cancers and for some cancers the prognosis is much better and for some much worse. However, when I started as a cancer researcher at the Department of Zoophysiology in 1979, the cancer survival rate was much worse. Thus, a lot has happened but there is still much to do.
Today we know that a cancer is a clump of heterogeneous cells meaning that the cancer cells of a tumour are different. There seems to be different degrees of aggressiveness in the different cancer cells. It has been hypothesized that the most aggressive cancer cells are resistant towards the chemotherapeutic drugs used today and also towards radiation. These very aggressive cells have been termed cancer stem cells (CSCs) because they have some properties that resemble them to normal stem cells, such as self-renewal and differentiation. CSCs were first found in leukaemia and have subsequently been found in solid tumours of the breast, pancreas, ovary, prostate, ovaries and brain. A new generation of thinking in cancer treatment focuses on attacking the roots of cancer, the CSCs.
Current Cancer Stem Cell projects
Firstly, we are investigating the effect of new potential chemotherapeutic drugs on the CSC population of breast cancer cell lines (but also of pancreas, ovarian and prostate cancer cell lines). Together with Doc. Daniel Strand at the Center for Chemistry and Chemical Engineering, Department of Chemistry, Lund University, we are investigating the potency and selectivity of salinomycin and chemically modified salinomycin derivatives on CSCs. In a SIDA-financed project, we are investigating how chemical compounds isolated from high-altitude plants in Bolivia affect CSCs. This project is done in cooperation with chemists and biologist at the Universität Mayor de San Andrésin, La Paz, Bolivia. In another project together with Prof. Marie Olsson at the Swedish University of Agricultural Sciences, Alnarp, we are investigating how Rose hip extracts affect CSCs. PhD students are involved in all of these projects.
Secondly, in the process of investigating the selectivity and potency of these compounds against CSCs we are also trying to understand the biology of CSCs by trying to deduce the mechanism of action of the compounds. We are using different kinds of methods to study cell proliferation and cell cycle kinetics, differentiation and cell death of CSCs isolated using flow cytometry and magnetic bead separation. Flow cytometry is a method we use a lot in applications of cell identity and function. Western blot is used to elucidate molecular pathways involved in the responses. We are using a new microscopic technique called phase holographic imaging to characterize CSCs non-invasively.
As experimental model systems we use cells growing in culture. We are mainly using cancer cell lines of various origin such as breast, prostate, pancreas, ovarian and colon cancer. In our work we are striving to reduce the use of animal-derived products and also to find ways to investigate off-target effects on normal cells. Thus, when we find new compounds with potential CSC inhibiting activity, we investigate toxicity on nerve cells, heart cells and liver cells. Our goal is to find new drugs for cancer treatment and today animal testing is required by the regulatory agencies. However, we involve a battery of normal cells in our search for new potential compounds to avoid unnecessary animal experiments. Only compounds that efficiently kill CSCs and do not show severe off-targets effects in our cell line-based tests will be suggested for advancement towards clinical use.
You are very well come to visit our outstanding cell culture facility for teaching and research at the Department of Biology, Sölvegatan 35, building C.
While medical procedures including surgery and radiation treatment are indispensable tools for cancer treatment, chemotherapy is often the only option for metastasized disease and the better alternative in terms of availability, cost and patient suffering.
According to some views, much focus the past 50 years has been devoted to agents that de-bulk tumors but do not remove the source of the problem, not unlike pruning trees rather than eliminating their roots – the tree will grow back bigger and stronger than before. Even early chemotherapeutics, as crude as nitrogen mustards, efficiently decrease tumor size. A common problem with such treatments is rapid and aggressive return of the disease, often in a form unresponsive to further treatment. A new generation of thinking in cancer treatment focuses on attacking the roots of cancer, the cancer stem cells (CSCs). CSCs are characterized by the ability of self-renewal, as well as the ability to spawn differentiated progeny (non-CSCs). Tumor growth and recurrence is at least in part driven by CSCs and CSCs are typically unresponsive to chemotherapy. A consequence of this unresponsiveness, in part driven by resistance and drug uptake problems, is that chemotherapy imposes a strong selection for CSC survival. CSCs have been found across several cancer types including breast, pancreas, ovary, prostate cancer, and more recently leukemia. Small molecules selectively targeting CSCs constitute a hereto-unexploited opportunity for prevention of cancer recurrence and metastasis, and imply opportunities in widening the range of useful chemotherapeutic agents. A 2009 report by Gupta, Weinberg and co-workers details the seminal find that salinomycin (SA), selectively reduces the number of breast CSCs over control cells. Specifically, SA reduced the proportion of breast CSCs in mice, two orders of magnitude more efficiently than clinically used paclitaxel. In 2012, SA entered preliminary clinical trials. The selectivity levels of the native structure is however currently limited to ~ 10 fold over the control cells at micro molar concentrations. These proof-of-principles however suggest that improved compounds with respect to selectivity and potency would have significant value, clinically and/or as a leads toward the identification of new venues for small-molecule elimination of the roots of cancer, the CSCs.
With its somewhat limited selectivity and an origin as a natural ionophore antibiotic, SA is unlikely to be an ideal candidate for clinical use in cancer treatment. We have therefore initiated an interdisciplinary program that aims to develop novel and superior structures for eradicating CSCs using a SA-informed approach. The synthesis driven approach that forms the basis for this proposal removes the limitation of studying only what is available or known (SA) and enables the study of unique designed structures (SA analogs). In a biological setting, the access to unique designed structures enables new ways of thinking about investigating the mechanisms through which SA selectively targets the CSC population.
- Zhen Li (PhD student)
- John Stegmayr (Post-doc)
- Zilma Escobar Gabriel (Post-doc)
- Cecilia Hegardt (Associate professor)
- Gloria Rodrigues (Associate professor)
- Karin Cederbrant (Associate professor)
- Giovanna Almanza (Professor)
- Thomas Helleday (Professor)
- Ulf Nilsson (Professor)
- Hakon Leffler (Professor)
- Olov Sterner (Professor)