Impact of MACC1 on human malignant glioma progression and patients' unfavorable prognosis

摘要

Metastasis-associated in colon cancer 1 (MACC1) has been established as an independent prognostic indicator of metastasis formation and metastasis-free survival for patients with colon cancer and other solid tumors. However, no data are available concerning MACC1 expression in human astrocytic tumors. Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor of adulthood, and due to its invasive and rapid growth, patients have unfavorable prognoses. Although these tumors rarely metastasize, their invasive and migratory behavior is similar to those of metastatic cells of tumors of different origin. Thus, we hypothesized that MACC1 may be involved in progression of human gliomas. Methods. We performed real-time measurements of proliferation and migration in MACCl-transfected GBM cell lines (U138, U251) and evaluated tumor formation in organotypic hippocampal slice cultures of mice. Semiquan-titative and quantitative real-time reverse transcription PCR analyses were performed for MACC1 and for its tran-scriptional target c-Met in human astrocytoma of World Health Organization grade Ⅱ (low-grade astrocytoma) and GBM biopsies. Data were validated by MACC1 immu-nohistochemistry in independent matched samples of low-grade astrocytoma and GBM. Results. MACC1 increases the proliferative, migratory, and tumor-formation abilities of GBM cells. The c-Met inhibitor crizotinib reduced MACC1-induced migration and tumor formation in organotypic hippocampal slice cultures of mice. Analyzing patients' biopsies, MACC1 expression increased concomitantly with increasing World Health Organization grade. Moreover, MACC1 expression levels allowed discrimination of dormant and recurrent low-grade astrocytomas and of primary and secondary GBM. Strong MACC1 expression correlated with reduced patient survival. Conclusions. MACC1 may represent a promising bio-marker for prognostication and a new target for treatment of human gliomas.