Impact of MACC1 on human malignant glioma progression and patients' unfavorable prognosis.
BACKGROUND
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 MACC1-transfected GBM cell lines (U138, U251) and evaluated tumor formation in organotypic hippocampal slice cultures of mice. Semiquantitative and quantitative real-time reverse transcription PCR analyses were performed for MACC1 and for its transcriptional target c-Met in human astrocytoma of World Health Organization grade II (low-grade astrocytoma) and GBM biopsies. Data were validated by MACC1 immunohistochemistry 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 biomarker for prognostication and a new target for treatment of human gliomas.
Corresponding Author: Ulrike Stein, PhD, Experimental and Clinical Research Center, Charité University Medicine Berlin and the Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany. ustein@mdc-berlin.de.
Carsten
C
Hagemann
Steffen
S
Fuchs
Camelia M
CM
Monoranu
Pia
P
Herrmann
Janice
J
Smith
Tim
T
Hohmann
Urszula
U
Grabiec
Almuth F
AF
Kessler
Faramarz
F
Dehghani
Mario
M
Löhr
Ralf-Ingo
RI
Ernestus
Giles H
GH
Vince
Ulrike
U
Stein
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D060787:Neoplasm Grading; D009924:Organ Culture Techniques; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D055815:Young Adult
D014408:Biomarkers, Tumor; C544162:MACC1 protein, human; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors
MACC1; astrocytoma WHO grade II; glioblastoma multiforme; prognostication; progression