Introduction: Matrix metalloproteinase 9 (MMP-9) impacts many physiological functions and is essential in extracellular matrix (ECM) restructuring. MMP-9 cleaves multiple collagen subtypes as well as chemokines and growth factors; it is secreted by white blood cells, endothelial cells (EC’s), and other cell types. EC MMP-9 production is triggered by TNF-a, VEGF, and FGF2 that impact physiologic and pathologic tissue remodeling. MMP9 also plays a role in tumor metastasis development. Elevated expression in various cancers has been noted; in colorectal cancer (CRC) patients (pts) plasma MMP-9 levels were shown to be elevated for 2 weeks after resection. This study’s objective was to determine if preoperative (preop) plasma levels of MMP-9 in CRC pts are elevated vs. preop levels in pts undergoing resection for benign colonic pathology (BCP).
Method: This study involved pts who underwent colorectal resection for CRC or BCP who also participated in an IRB approved tissue/data bank for whom preop plasma samples were available. Demographic, clinical and pathological data were assessed. Preop plasma MMP-9 levels were determined via ELISA and results reported as median ±95% CI (ng/ml). The expression of MMP-9 mRNA in CRC and adjacent normal tissues was determined via QRT-PCR and protein expression assessed via immunohistochemistry (IHC) on tissue sections for a subset of patients. The potential of plasma MMP-9 as a CRC diagnostic marker was assessed using the Receiver Operating Characteristic (ROC) curve and area under the ROC curve (AUC). The Mann-Whitney test was used for statistical analysis (p <0.05 significant).
Results: The study assessed 116 pts with CRC (66% colon and 34% rectal) and 102 pts with BCP (26% adenomas, 65% diverticulitis, and 9% other). Male to female ratios were similar yet CRC pts were older (p=0.003). The cancer stage distribution was as follows: stage 1: 32%, Stage 2: 25%, stage 3: 34%, and stage 4: 7%. Median plasma MMP9 levels were markedly higher in CRC pts compared to the BCP group (133.1, CI: 112.6-161.2 vs 95.8, CI: 68.2-142.8; p<0.001). Non-significant increases in mean MMP9 levels were noticed between Stage 2 and 4 pts vs Stage I pts. The AUC value for the ROC curve was 0.636, with a sensitivity of 79% and a specificity of 44%. 83% of tested CRC tumors (10/12) exhibited higher MMP9 expression compared to matched normal tissues.
Conclusion: Median MMP-9 levels were 38 % higher in CRC pts vs results in BCP pts. Increased MMP9 levels in CRC was confirmed via IHC. Analysis of the ROC curve suggests that preop plasma MMP-9 levels alone as a diagnostic tool is not promising. Plasma elevations may be related to increased MMP9 levels noted in tumor samples. Elevated MMP-9 levels potentially aid in new blood vessel formation and tumor growth. Further research is needed.
