Laboratory for Experimental Oncology and Radiobiology

The laboratory of experimental oncology and radiobiology is a multi-disciplined laboratory that focuses on cell death induction and resistance in tumors. In their seminal paper, “The hallmarks of cancer”, Hanahan and Weinberg described resistance to cell death (apoptosis) as one of the crucial steps in the development of cancer. Besides being involved in tumor initiation, this cell death resistant phenotype will also influence the effectiveness of treatment modalities that often rely on triggering the intrinsic cell death machinery. As such, the mechanisms by which tumors escape cell death and exploration of treatments that circumvent or alleviate resistance are important for the development of novel anti-cancer therapies. Within the laboratory we have several programs that address the questions of cell death in tumors and these are described in detail below.

APRIL

APRIL stands for a proliferation inducing ligand and is a member of the tumor necrosis factor family. It is a secreted protein and derives its name from the observation that it can induce growth, but also survival, in a wide range of tumors. Moreover, we have shown that APRIL is expressed by a variety of tumors at relatively high incidence and could thus drive tumor growth in an autocrine manner in patients. In agreement, APRIL transgenic mice develop B lymphoid malignancies (fig 1). These mouse lymphomas are reminiscent of a human chronic lymphocytic leukemia, which is indeed associated with high circulating levels of APRIL in the blood of patients.
Despite the clear role of APRIL in cancer, its mechanism of action and the receptor through which it stimulates tumors remain poorly defined. Our laboratory therefore focuses on the signal transduction elicited by APRIL, the receptors involved, but is also developing APRIL blocking agents to determine the therapeutic value of APRIL antagonism.

Cancer Stem Cells

The classical view of tumors describes that all cells within a tumor have the capacity to grow out to form a new tumor and that the heterogeneity within a tumor is a result of the accumulation of novel mutations. However, recent results have suggested the existence of cancer stem cells (CSC) that drive the growth of tumors, while the more differentiated cells have lost the clonogenic capacity. As CSC only constitute a small percentage of the total tumor mass this has prompted a revised view on tumor biology. Instead of picturing tumors as a mass of cells that have unlimited growth capacity, cancer may better be regarded as an abnormal organ in which growth is driven by a population of CSC and where most cells have a more differentiated phenotype and are no longer capable of tumor formation. This view has important implications as it suggests that CSC are the only cells capable of forming metastasis and should be the target of anti-tumor therapies. Although this revised view on tumor development and growth is still debated, we have been able to isolate and culture cells with cancer stem cell features from different human tumor samples (fig. 2). These cells display specific cell death resistant features, but are capable of forming tumors. This program attempts to further characterize these CSC, their cell death resistant aspects and their role in tumor growth and resistance.

Radiobiology

This research area investigates the biological effects of radiation (ionizing radiation such as ?-rays, X-rays and α-particles, but also electromagnetic radiation as used in hyperthermia) in cells, tissue and organisms. The radiobiology research in the AMC is aimed at understanding the mechanisms of cellular radiosensitivity in order to find opportunities to improve the outcome of radiation oncology treatment. Since radiotherapy is a localized treatment modality, we focus on the question why local tumor control is not always achieved. Our hypothesis is that non-proliferating tumor cells are the main cause for a local recurrence because of their capacity to repair radiation-induced DNA damage. The interaction with other treatment modalities (e.g. chemotherapy) is investigated to increase the effectiveness of radiation. Radiation-induced chromosomal aberrations (Fig.3) are used to study the mechanism of repair of radiation-induced DNA damage as well as to predict cellular radiosensitivity.

This research area investigates the biological effects of radiation (ionizing radiation such as ?-rays, X-rays and α-particles, but also electromagnetic radiation as used in hyperthermia) in cells, tissue and organisms. The radiobiology research in the AMC is aimed at understanding the mechanisms of cellular radiosensitivity in order to find opportunities to improve the outcome of radiation oncology treatment. Since radiotherapy is a localized treatment modality, we focus on the question why local tumor control is not always achieved. Our hypothesis is that non-proliferating tumor cells are the main cause for a local recurrence because of their capacity to repair radiation-induced DNA damage. The interaction with other treatment modalities (e.g. chemotherapy) is investigated to increase the effectiveness of radiation. Radiation-induced chromosomal aberrations (Fig.3) are used to study the mechanism of repair of radiation-induced DNA damage as well as to predict cellular radiosensitivity.

Members of the laboratory

  • Jan Paul Medema (group leader)
  • Klaas Franken (staff)
  • Catarina Grandela (postdoc)
  • Fiona Kimberley (postdoc)
  • Maarten Bijlsma(postdoc)
  • Michael Bots (postdoc)
  • Cheryl Zimberlin (PhD student)
  • Dita Prasetyanti (PhD student)
  • Evelyn Kessler (PhD student)
  • Felipe de Sousa E Melo (PhD student)
  • Helene Damhofer(PhD student)
  • Kristel Kemper (PhD student)
  • Lisette Potze (PhD student)
  • Louis Vermeulen (PhD student)
  • Marco Gaudagnoli (PhD student)
  • Melania Balzarolo (PhD student)
  • Selcuk Colak PhD student)
  • Suzanne Hovingh PhD student)
  • Tijana Borovski (PhD student)
  • Valeria Lascano (PhD student)
  • Hans Rodermond (technician)
  • Joan de Jong (technician)
  • Kate Cameron (technician)
  • Rosemarie Ten Cate (technician)
  • Saskia van den Bergh (assistant-technician)

Prizes/Scholarships/Awards

  • KWF fellowship 1996-1998
  • VIDI recipient 2000
  • C.J.Kok prize 2002
  • VICI recipient 2007