Abstract 2444: Plasma levels of matrix metalloproteinases 8 are significantly increased in patients with colorectal cancer (CRC) and mRNA levels are increased in 71% of tumors vs normal tissue
Authors: Mudiyanselage Chandana S. K. Herath , Sharma Anuj R. , Mitra Neil , Sah Aashutosh , Yan Xiaohong , Palacios Pablo , Cekic Vesna , Whelan Richard L. 
Published: March 2024

Introduction: Matrix metalloproteinases 8 (MMP-8) is a member of the MMP protease family mainly involved in degrading extracellular matrix. A variety of cells express MMP-8 and during pathological inflammation neutrophils release IL-1, IL-8, TNF-α, and GM-CSF which triggers MMP-8 secretion. MMP-8 aids tumors in evading immune detection during the development of CRC and also regulates the role of endothelial cell in angiogenesis. Increased MMP-8 tumor expression and serum levels has been noted in hepatocellular cancer and melanoma patients and are associated with adverse outcomes. There is limited data regarding blood levels of MMP-8 in CRC patients. This study compared preoperative (PreOp) plasma MMP-8 levels in patients with CRC and benign colonic pathology (BCP) undergoing bowel resection.

Method: Patients with CRC or BCP who had elective colorectal resection who were enrolled in an IRB approved tissue and data bank for whom preop plasma samples were available were eligible. Data analyzed included demographic, clinical, operative, and final pathology reports. Blood specimens were quickly processed and plasma stored at -80°C. MMP-8 levels in Preop plasma samples were measured via ELISA, in duplicate, and reported as median +95% CI (ng/ml). MMP8 expression was examined in paired CRC and normal mucosal tissue samples from a subset of the CRC patients (n=20) via QRT-PCR. Immunohistochemistry (IHC) was conducted on formalin-preserved tissue sections (tumor/normal pairs) following standard protocols. The concept of MMP8 as CRC diagnostic marker was evaluated by assessing the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC). The analysis was done with the Mann-Whitney test (significance, p&lt;0.05).

Results: 96 CRC patients (74% colon and 26% rectal cancer) and 96 BCP patients (32% adenoma, 64% diverticulitis, 4% other) met entry criteria. The CRC stage distribution was: Stage 1, 26%; Stage 2, 26% Stage 3, 40%; and stage 4, 8%. Median plasma MMP-8 levels were higher in CRC (8.21, CI: 6.92, 10.81) compared to BCP patients (5.59, CI: 4.68, 7.30; p&lt;0.001). A non-significant increase in median MMP-8 levels were noted in STG IV vs STG I and STG II and STG III was found (38-89%). IHC validated the expression of MMP-8 in CRC tumors relative to normal colon. Increased expression of MMP-8 was seen in 71% of the tested CRC samples (12/17). The AUC value for the ROC curve was 0.653 (sensitivity 35%, specificity 0.95%).

Conclusion: The median MMP-8 level in CRC patients was found to be 47% higher compared to BCP patients and 89% higher in stage IV vs stage II patients (p=0.06). The tumor is the most likely the cause of elevated plasma levels. Increased tumor expression of MMP-8 mRNA was noted in 71% of tumors. The low sensitivity of the ROC curve suggests MMP8 alone has no value as diagnostic factor. Larger studies are justified.

Citation Format: Chandana S. K. Herath Mudiyanselage, Anuj R. Sharma, Neil Mitra, Aashutosh Sah, Xiaohong Yan, Pablo Palacios, Vesna Cekic, Richard L. Whelan. Plasma levels of matrix metalloproteinases 8 are significantly increased in patients with colorectal cancer (CRC) and mRNA levels are increased in 71% of tumors vs normal tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2444.