Clinical Research Programme

Stem Cells and Cancer Clinical Research Unit

• Stem Cells and Cancer Clinical Research Unit
• Overview
• Personnel
• Publications
Head of Unit:  Christopher Heeschen

Overview Last update 08/01/2009
During the past decade, the concept of cancer stem cells has regained enormous attention. Indeed, the cytoprotection afforded by stem cells quiescence in stress-free, steady state conditions suggests a mechanism through which potentially dangerous lesions can accumulate in these tissue-resident somatic stem cells with age and during chronic inflammatory states. Recently, we have been able to define the role of pancreatic cancer stem cells in tumor growth and metastasis (Hermann et al., 2007; Hermann et al., 2008) (Fig. 1)
 
 
Based on these data, it is now important that we are further aiming for a better understanding of the origin of these cancer stem cells, which may also guide us to new therapeutic strategies to prevent the transformation of tissue-resident somatic stem cells. In parallel, we have initiated comparative functional and genomic analyses of the identified human CSC populations, their more differentiated progenies, normal tissue resident stem cells, and hematopoietic stem cells. For these analyses, we are particularly focusing on the demonstrated resistance of cancer stem cells to chemotherapy, radiation, and immunotherapy, respectively, as well as their invasive properties and tumor-initiating capacity as demonstrated in our orthotopic mouse models. In this context, it is important to note that cancer stem cells may be located and protected in a perivascular niche provided by the tumor vasculature. The subsequent functional characterization of newly identified genes and their biological function in respect to tumor angiogenesis, invasiveness, and metastasis for (pancreatic) cancer should provide us with new cognitions about the role of cancer stem cells in cancer biology.
Cancer stem cell in (pancreatic) cancer. It is a well-known fact that normal tissues as well as the related tumor tissues are comprised of a heterogeneous accumulation of cell types including immune cells, stroma with mesenchymal and endothelial cells and several tissue-specific malignant cells (Brabletz et al., 2005; Dalerba et al., 2006; Dick, 2005; McDonald et al., 2006). Apparently, cells in a tumor seem to match different stages of development. Epithelial tumors for example contain cells with divergent nuclear morphologies and signs of differentiation. Until now, the predominant explanation for tumor heterogeneity was influence of the microenvironment and genomic instability leading to genetic and epigenetic alterations, thus preventing reliable and accurate replication and transmission of a stable genotype and phenotype. Such instability could explain the observation that most tumors contain a distinct subpopulation that is resistant to most therapies. However, there is a different (or complementary) concept, which may also explain this observation. According to this concept, malign cell populations show a continually defective differentiation process, while a small population of so called CSCs gives rise to the development of a hierarchy of heterogeneous cell types but is not necessarily derived from the tissue resident stem cells (Fig. 2).
 
 
What is the current definition of these cancer stem cells? The current consensus definition describes a CSC as a cell within a tumor, which is able to self-renew and to produce the heterogeneous lineages of cancer cells that comprise the tumor. Thus, cancer stem cells can only be defined experimentally by their ability to recapitulate the generation of a continuously growing tumor, which can be serially transplanted. The implementation of this approach explains the use of alternative terms in the literature, such as “tumor-initiating cell” and “tumorigenic cell” to describe putative cancer stem cells (Clarke et al., 2006).
The origin of cancer stem cells, though, remains unclear for most malignancies. Basically there are at least two possible scenarios. On the one hand, there could be a process of de-differentiation of already committed progenitor cells providing them the capacity for unlimited self-renewal (Fig. 3). On the other hand, cancer stem cells could indeed originate directly from tissue stem cells. The fact that 3 to 6 genetic mutations are necessary to transform a normal human cell into a cancer cell rather supports the latter theory. Development of transformed cells should take at least months, if not years. As many differentiated cells are only able to renew themselves for a couple of weeks, it is likely that they do not exist long enough to accumulate multiple genetic changes. Alternatively, the initiating mutation could take place in tissue stem cells endowing them with uncontrolled self-renewal, while subsequent mutations in their respective daughter cells may then also occur, leading for fully transformed cells. According to a recent publication, there are indeed hints for the function of such a tissue-based stem cell compartment during the development of lung cancer (Kim et al., 2005). Based on the presented data, stem cells seem to play a pivotal role both in lung tissue regeneration and tumorigenesis.
 
 
Together, the above experiments should generate important clues how these cells circumvent the physiological regulatory elements of stem cell functionality and, even more importantly, how these cells escape the response to standard cancer therapy. Eventually, these new insights may allow us to develop novel targeted and multimodal treatment modalities for the successful elimination of these cells as the previously unrecognized root of the tumor. One possibility to achieve this treatment goal would be to inhibit the self-renewal capacity of cancer stem cells without affecting the normal stem cell pool. On the other hand, inducing CSC differentiation and thus eliminating their potential to self-renew (differentiation therapy) also appears as a promising strategy. Based on our current knowledge about the nature of cancer stem cells, we expect that multimodal therapies will be necessary to control their uncoupled self-renewal capacity (Fig. 4).
 
 
Of note, only those patients should be exposed to specific targeted treatments that actually derive a clinical benefit from the individual treatment modality. Therapeutic responsiveness of the individual patient could be predicted by the in vitro exposure of patient-derived CSC spheres to different treatment modalities helping for the selection of the optimal treatment regimen. This would maximize the treatment efficacy for the individual patient and, equally important, will avoid the risk of undesired side effects by treatment modalities that essentially do not generate a therapeutic benefit in other patients (tailored therapy).
Pancreatic ductal adenocarcinoma. Pancreatic cancer is the fourth leading cause of cancer-relative deaths. The number of diagnoses per year virtually equals the number of deaths per year, making it the deadliest of all malignancies. In Europe, the incidence of pancreatic cancer for men is 14.4 and for women 18.3 new diseases per 100,000 citizens/year (year 2000). The age peak of diagnosis is 65 years and a major risk factor is smoking. The disease is characterized by extensive local infiltrating growth as well as early lymphatic and hematogenic metastasis (Brand and Tempero, 1998; Wanebo and Vezeridis, 1996). At the time of diagnosis, the disease is localized solely in the pancreas in less than 20% of the patients. 40% of the patients have locally advanced cancer, and the remaining 40% already show visceral metastases (Brand and Tempero, 1998; Burris et al., 1997; Wanebo and Vezeridis, 1996). Lacking early diagnostic tools, considering the aggressiveness of the disease and the inefficiency of current systemic therapies, the incidence rate in pancreatic cancer is almost identical with the mortality rate. The 5-year survival rate for adenocarcinomas of the exocrine pancreas is still only 1–5% (Ahlgren, 1996; Rothenberg et al., 1996); the median survival time of patients with metastatic disease is only 5 months (Hedberg et al., 1998; Rosewicz and Wiedenmann, 1997; Warshaw and Fernandez-del Castillo, 1992), in spite of many different palliative therapeutic concepts (Fig. 5).