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Expression patterns of LIS1, dynein and their interaction partners dynactin, NudE, NudEL and NudC in human gliomas suggest roles in invasion and proliferation

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Abstract

Diffusely infiltrating gliomas are the most common type of primary intracranial neoplasm in humans. One of the major obstacles to the effective treatment of these tumors is their highly infiltrative growth. However, mechanisms controlling their migration and proliferation are poorly understood. Glioma cells resemble neural progenitors, and we hypothesize that gliomas recapitulate the capacity of migration and proliferation of progenitors that takes place during brain development. Based on recent evidence implicating cytoplasmic dynein and its regulatory proteins in neural progenitor migration and division, we conducted immunohistochemical evaluation of surgically resected human glioma samples for the presence and distribution of these proteins. We examined expression of LIS1, the gene responsible for type I lissencephaly, cytoplasmic dynein and the dynein- and LIS1-interacting factors dynactin, NudE/NudEL and NudC, which play significant roles in neural progenitor cell behavior. We found that each of these proteins is expressed in all histological types and grades of human neuroectodermal tumors examined. Immunohistochemical analysis revealed that the levels of expression varied from cell to cell within each tumor, ranging from very high to undetectable. This stands in contrast to the low levels of diffuse staining seen in non-neoplastic brain tissue. Of particular interest, we noted tumor cells infiltrating the white matter and tumor cells undergoing cell division amongst the cells with notably high expression levels. These findings are compatible with the idea that LIS1 and its interacting proteins play a role in glioma migration and proliferation analogous to their role during brain development.

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Acknowledgments

Authors thank Bridget Shafit-Zagardo (Montefiore Hospital) for generously providing MAP-2e antibody, Barbara Miller (Penn State University) for anti-NudC antibody, Kevin Vaughan (Notre Dame University) for anti-dynein intermediate chain antibody and Kenta Masui, Kazue Hatanaka and Rumiko Kuroki in the Department of Neuropathology, Takaaki Kanemaru in the Morphology Core, Kyushu University for their excellent technical assistance.

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Authors and Affiliations

  1. Department of Neuropathology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan

    Satoshi O. Suzuki, Shin-ya Mawatari & Toru Iwaki

  2. Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, USA

    Richard J. McKenney, Atsushi Mikami, James E. Goldman, Peter Canoll & Richard B. Vallee

  3. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Masashi Mizuguchi

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  1. Satoshi O. Suzuki
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Correspondence to Satoshi O. Suzuki.

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This work was supported in part by a Grant-in-Aid for Scientific Research (no. 16500202) from the Japanese Ministry of Education, Culture, Sports, Science and Technology to SOS and NIH grant HD40182 to RBV.

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Fig4

Supplemental Fig. 1 Comparison of staining patterns with antibodies raised against different epitopes of LIS1 and DHC. Comparative staining patterns were obtained with the set of antibodies for each protein. DHC#46 stains only frozen but not paraffin sections. DHC#46 antibody gave higher background staining probably due to better antigen preservation in frozen sections, however, the intense staining of the cytoplasm and fibrillary processes of each tumor cell was commonly seen in DHC#8- and #43-staining, which we think to be the specific expression pattern of DHC. Bar=100mm for LIS1 antibodies and 30mm for DHC antibodies.

Fig5

Supplemental Fig. 2 Expression of dynein and its regulatory proteins in astrocytic tumors. a, pilocytic astrocytoma. Long, bipolar processes of pilocytic astrocytoma cells are delineated. b, diffuse astrocytoma. Some of the tumor cells show simple, uni- or bipolar morphology, while others show multipolar morphology. c, anaplastic astrocytoma. A majority of the tumor cells show cytoplasmic staining particularly in those with gemistocytic morphology. d, glioblastoma. Highly anaplastic tumor cells including multinucleated giant cells are immunopositive. . IC: dynein intermediate chain, DHC: dynein heavy chain. Bar=50mm for a, c, and d, 25mm from b.

Fig6

Supplemental Fig. 3 Expression of dynein and its regulatory proteins in other glial or glioneuronal tumors. a, ependymoma. Perivascular processes of the tumor cells are immunopositive. Diffuse areas tend to stain more weakly. b, gliosarcoma. Both gliomatous and sarcomatous components are immunopositive. c, oligodendroglioma. Tumor cells with typical perinuclear halo weakly stain. d, ganglioglioma. Both astrocytoma cells and ganglion cells are immunopositive. IC: dynein intermediate chain, DHC: dynein heavy chain. Bar=50mm for a-c, 25mm for d.

Fig7

Supplemental Fig. 4 Expression of dynein and its regulatory proteins in non-tumoral adult human brain tissue represented by LIS1 immunohistochemistry. a, the cerebral cortex from a patient with temporal lobe epilepsy. LIS1 is expressed in soma of the large pyramidal neurons (large arrow heads) as well as small-sized neurons (small arrow heads). Note the weak, diffuse staining in the neuropil. No staining indicating protoplasmic, non-reactive cortical astrocytes is observed. b, reactive astrocytes in the hippocampus with mesial temporal sclerosis (arrows). Bar=50mm for a, 33mm for b.

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Suzuki, S.O., McKenney, R.J., Mawatari, Sy. et al. Expression patterns of LIS1, dynein and their interaction partners dynactin, NudE, NudEL and NudC in human gliomas suggest roles in invasion and proliferation. Acta Neuropathol 113, 591–599 (2007). https://doi.org/10.1007/s00401-006-0180-7

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