Tumor epithelial cell matrix metalloproteinase 9 is a target for antimetastatic therapy in colorectal cancer.
BACKGROUND
The current paradigm suggests that matrix metalloproteinase 9 (MMP-9) expressed by stromal cells is a therapeutic target in human colorectal tumors which presumably regulates metastatic disease progression. Conversely, whereas cancer cells within those tumors may induce stromal cells to produce MMP-9 and may be targets for MMP-9 activity, they are not the source of MMP-9 underlying metastasis.


METHODS
MMP-9 expression in matched colorectal tumors and normal adjacent mucosa from patients and human colon cancer cell lines was examined by real-time reverse transcription-PCR, laser capture microdissection, immunoelectron microscopy, and immunoblot analysis. The role of colon cancer cell MMP-9 in processes underlying metastasis was explored in vitro by examining degradation of extracellular matrix components by gelatin zymography and formation of locomotory organelles by cell spreading analysis and in vivo by quantifying hematogenous tumor cell seeding of mouse lungs.


RESULTS
Primary colorectal tumors overexpress MMP-9 compared with matched normal adjacent mucosa. In contrast to the current paradigm, MMP-9 is expressed equally by cancer and stromal cells within human colon tumors. Cancer cell MMP-9 regulates metastatic behavior in vitro, including degradation of extracellular matrix components and formation of locomotory organelles. Moreover, this MMP-9 critically regulates hematogenous seeding of mouse lungs by human colon cancer cells in vivo.


CONCLUSIONS
These observations reveal that MMP-9 produced by human colon cancer, rather than stromal, cells is central to processes underlying metastasis. They underscore the previously unrecognized potential of specifically targeting tumor cell MMP-9 in interventional strategies to reduce mortality from metastatic colorectal cancer.
Division of Clinical Pharmacology, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Wilhelm J
WJ
Lubbe
Zengyi Y
ZY
Zhou
Weili
W
Fu
David
D
Zuzga
Stephanie
S
Schulz
Rafael
R
Fridman
Ruth J
RJ
Muschel
Scott A
SA
Waldman
Giovanni M
GM
Pitari
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D020780:Matrix Metalloproteinase 9