A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer.
OBJECTIVE
Loss of the basement membrane (BM) is considered an important step toward tumor malignancy. However, the BM is still expressed in most typical colorectal adenocarcinomas; nevertheless, these tumors can invade and develop metastases. The aim of this study was to investigate the role, mechanisms, and clinical relevance of BM turnover in malignant colorectal cancer (CRC) progression.


METHODS
Expression of BM components and their transcriptional regulation and clinical relevance were investigated in human CRCs and cell lines.


RESULTS
Our data show new aspects in BM turnover in CRCs with impact on malignant tumor progression: (1) The BM is still expressed in the main tumor mass of most colorectal adenocarcinomas, but selectively lost at invasive regions of the tumor in many cases. (2) Selective loss of the BM at the invasive front has high clinical and tumor biologic relevance for distant metastasis and survival. (3) The BM is reexpressed in metastases, indicating that its loss is transient and regulated by environmental factors. (4) This transient loss is not only due to proteolytic breakdown but to a down-regulated synthesis and linked to an epithelial-mesenchymal transition (EMT) in tumor cells, and, thereby, zinc-finger-enhancer protein 1 (ZEB1) is the crucial transcriptional repressor of BM components in CRCs.


CONCLUSIONS
A transient BM loss at the invasive front is correlated with increased distant metastasis and poor patient survival, indicating its tumor biologic relevance and usefulness as a prognostic marker. Targeting ZEB1 might be a promising therapeutic option to prevent metastasis.
Spaderna
Simone
S
Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany.
Schmalhofer
Otto
O
Hlubek
Falk
F
Berx
Geert
G
Eger
Andreas
A
Merkel
Susanne
S
Jung
Andreas
A
Kirchner
Thomas
T
Brabletz
Thomas
T
D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality* / Q000556:secondary*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001485:Basement Membrane / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D005500:Follow-Up Studies; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1
D004273:DNA, Neoplasm; D018398:Homeodomain Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1