The Department of Biomedicine

BBB seminar: Tilo Wolf Eichler

Paraneoplastic neurological disorders: when the body damages itself in the battle against cancer

Tilo Wolf Eichler
Department of Clinical Medicine, University of Bergen

Paraneoplastic neurological disorders (PNS) are autoimmune side-effects of a cancer. The immune system reacts to a neoplasm (tumor) with the production of antibodies. In this way many neoplasms can be removed before a cancer can arise. Nevertheless, about 1% of cancer patients develop PNS when the immune reaction crosses the blood-brain barrier and damages parts of the CNS. The antibodies involved in PNS are very specific and used for diagnosis of the type of PNS and the underlying cancer. Paraneoplastic cerebellar degeneration (PCD) is the most common form of PNS and the center of our research.

Our field of interest is the characterization of the proteins that serve as antigens in cancer recognition, but which also occur naturally in neuronal cells. PCD is most often associated with gynecological cancer of breast or ovaries. The affected cells are Purkinje cells in the cerebellum, the largest neurons in the brain. All signals for coordinated movement go through these cells. In PCD Purkinje cells are destroyed by antibodies by a mechanism not fully understood. There are three proteins involved in PCD, called cerebellar degeneration related proteins (CDR). The antibodies against CDR proteins are referred to as Yo antibodies. Symptoms of PCD often precede the symptoms of the underlying cancer, making the screening for CDR antibodies a potential diagnostic tool. The detection of Yo antibodies in a PCD patient without a known cancer enables the detection and removal of this cancer before it shows any pathology. However, since the symptoms of PCD arise from destruction of neuronal tissue, the neurological symptoms can not be reversed. The only treatment available is removal of the tumor and thereby removing the source of the immune reaction, keeping the PCD in its current state.

We could show that CDR2 and CDR2L most often co-exist in PCD patients and that CDR2L is located to cell surface and cytoplasmic organelles, while CDR2 is manly located in cytoplasmic organelles and the nucleus. The exact localization has yet to be determined. CDR antibodies seem to interfere with calcium homeostasis and thereby damaging Purkinje cells. Overexpression of CDR1 in HeLa cells leads to a sudden cell death, but not overexpression of CDR2 or CDR2L. The mechanism of cell death has to be investigated further. The understanding of the function of CDR proteins and the highly specific interaction between cancer and PCD might contribute to better methods of treatment and diagnosis of both diseases.

Chairperson: Christian A. Vedeler <christian.vedeler@uib.no>, Department of Clinical Medicine