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Association of stem cell marker CD133 expression with dissemination of glioblastomas

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Abstract

Dissemination of glioblastoma was once considered rare but is now increasingly encountered with longer survival of glioblastoma patients. Despite the potential negative impact of dissemination on clinical outcome, however, molecular markers useful for prediction of dissemination risk still remains ill defined. We tested in this study for an association between the expression of stem cell marker CD133 and the risk of dissemination in 26 cases of glioblastoma (16 with dissemination and 10 without dissemination). The protein expression of CD133 was examined by western blot analysis of tumor specimens, and the CD133 expression levels were quantified by densitometry and normalized to β-actin. The results indicated that CD133 expression levels are significantly higher in glioblastomas with dissemination (mean 10.3, range 0.20-27.8) than in those without (mean 1.18, range 0.07-3.58). The results suggest that CD133 could be a molecular predictor of glioblastoma dissemination, and also give rise to an intriguing idea that CD133-positive cancer stem cells may be implicated in the initiation of disseminated lesions.

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Authors and Affiliations

  1. Department of Neurosurgery, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan

    Atsushi Sato, Kaori Sakurada & Takamasa Kayama

  2. Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

    Toshihiro Kumabe & Teiji Tominaga

  3. Department of Neurosurgery, Akita University School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan

    Toshio Sasajima & Kazuo Mizoi

  4. Department of Neurosurgery, Iwate Medical University, 19-1 Uchimaru, Morioka, 020-8505, Japan

    Takaaki Beppu & Akira Ogawa

  5. Department of Neurosurgery, Hirosaki University School of Medicine, Zaifu-cho 5, Hirosaki, 036-8562, Japan

    Kenichiro Asano & Hiroki Ohkuma

  6. Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585, Japan

    Chifumi Kitanaka

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  1. Atsushi Sato
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Additional information

Comments

Karl Frei, Zurich, Switzerland

In this study, the authors tested for an association between the expression of the stem cell marker CD133 and the risk of dissemination in 26 cases of glioblastomas (10 without and 16 with dissemination). The tumor specimens were examined by western blot analysis and the CD133 expression levels were quantified by densitometry and normalized to β-actin.

The authors suggest from their data that CD133 might be a molecular predictor of glioblastoma dissemination and that CD133-positive cancer stem cells may be implicated in the initiation of disseminated lesions.

This intriguing idea has to be taken with caution due to the following reasons:

1. The study is only based on western blot analysis and no immunohistochemistry has been performed to confirm the biochemical data.

2. The western blot analysis was not done in a quantitative manner.

The number of 26 cases is low and the observed variability (five negative cases in each group) high.

Comments

Oliver Heese, Hamburg, Germany

In this study, the authors investigated the association between the expression of CD133 and the risk of tumor dissemination in 26 cases of glioblastoma multiforme in order to identify new potential predictors of an unvaivorable outcome of this tumor. The CD133 expression was measured on protein level by western blot. Dissemination was defined as appearance of enhanced nodules and/or diffuse enhancement of the leptomeningeal space at distance sites of the primary tumor location on contrast enhanced MRI.

The results indicated that significant higher CD133 level were found in GMB patients with a disseminated tumor progression. These findings imply that high levels of CD133 expression may be associated with a high risk of dissemination whereas low CD133 expression may not exclude the possibility of dissemination.

Despite the recent surge of interest in CD133+ brain tumor stem cells, the clinical significance of this cell population remains unclear and with this study an interesting hypothesis is made. Striking evidence suggests a dynamic process of expression of CD133 positive cells.

Since the amount of CD133 positive cells may vary in a process of tumor progression the measured western blot data of the initial tumor specimen may not represent the amount of CD33 positive cells during tumor dissemination or during local tumor progression. In addition for future analysis, in order to correlate the relationship between CD133 expression and clinical prognosis not only the quantity of CD133 positive cells should be taken into account but also the quality of CD133+ cells in in vitro and in vivo model systems have to be evaluated.

Since various regimens target local tumor control of glioblastomas such as radiosurgery or local chemotherapy, disseminated tumor growth is difficult to treat and predictors are important in order to indentify this subpopulation of patients and CD133 expression may be one molecular parameter for prediction of the clinical course of a glioma patient group.

Comments

Michel Mittelbronn, Frankfurt, Germany

In their current manuscript, Sato et al. present CD133 as a molecular predictor for glioblastoma dissemination and suggest that CD133-positive stem cells may be implicated in the initiation of disseminated lesions. This very interesting finding might be—if constantly reproducible—a useful tool for the prediction of glioma growth and could impinge on treatment strategies. However, what is not proven in the present study and probably unprovable to date, is the open question if CD133 upregulation in glioblastoma is the cause of dissemination or rather a bystander effect or consequence of other conditions within gliomas. The authors strongly favor the hypothesis that the source of CD133 expression might be related to tumor stem cells (although not proven by means of immunohistochemistry or FACS analysis). Subsequently, I would like to provide some additional interpretation of the western blot data. CD133 is frequently considered as a marker for neural, hematopoietic, and brain tumor initiating stem or progenitor cells, however, the distribution of CD133 expression in brain tumors has remained controversial. CD133-positive cells not closely related to tumor vessels have been reported to reside in pseudopalisading areas of necrosis (1). These areas are mainly subjected to low oxygen concentrations. From cell experiments, it is known that cultured glioma cells are capable to express CD133 when kept under hypoxic conditions without immediately being considered as stem cells (2, 3). Furthermore, emerging studies point out that anti-angiogenic approaches in high grade gliomas either lead to (1) reactivating angiogenesis through upregulation of other proangiogenic factors, (1) invading normal CNS tissue via upregulation of matrix metalloproteinases-2, 9, 12, and sparc (secreted protein, acidic, cysteine-rich) or even drive expression of critical genes associated with aggressiveness, invasiveness and poor survival in glioma patients (4, 5). Taking into account the fact that glioma cells upregulate CD133 under hypoxic conditions and that hypoxia strongly leads to a more migratory phenotype, one could assume that the findings of Sato et al. could more likely reflect a secondary CD133 upregulation in more migratory or disseminating glioblastomas.

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Sato, A., Sakurada, K., Kumabe, T. et al. Association of stem cell marker CD133 expression with dissemination of glioblastomas. Neurosurg Rev 33, 175–184 (2010). https://doi.org/10.1007/s10143-010-0239-8

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