MICR is associated with significantly elevated plasma osteopontin levels during the 1st month after surgery which may promote cancer recurrence & metastasis

Hmc Shantha Kuamra, PhD1, Hiromichi Miyagaki, MDPhD2, Sajith A Herath, BS1, David Gaita, BS1, Xiaohong Yan, PhD1, Linda Njoh, PhD1, Vesna Cekic, RN1, Nipa D Gandhi, MD1, Richard L Whelan, MD1. 1Deaprtment of Surgery,Mount Sinai Roosevelt Hospital Center,New York,USA, 2Department of Gastroenterological surgery,Osaka University, Osaka, 565-0871 Japan

Introduction: Osteopontin (OPN), also known as early T lymphocyte activation-1, is an integrin binding phosphorylated glycoprotein secreted by activated macrophages and leukocytes; it is found in extracellular fluids, sites of inflammation and in the bone marrow. Various forms of CD44 serve as receptors for OPN. OPN mediates cell-matrix and cell-cell communication to support adhesion and targeted migration. OPN, expressed by a number of cancers including colorectal cancer, enhances tumor progression and angiogenesis via the PI3K/AKT and ERK mediated pathways in concert with VEGF. OPN also plays a role in wound healing (tissue remodeling) and OPN mutant rodents exhibit impaired wound healing. The impact of MICR for colorectal cancer (CRC) on plasma OPN levels is unknown. This study’s goal was to assess blood levels during the first month after MICR for CRC.

Method: Patients undergoing MICR (laparoscopic assisted + hand-assisted lap.) for CRC who were enrolled in an IRB approved tissue/prospective data bank for whom preoperative (PreOp) and postoperative (postop) plasma were available were eligible. Only patients for whom PreOp, Postop Day (POD) 1, POD 3 and at least 1 late postop plasma sample (POD7-34) were available were studied. The late samples were bundled into 4 time periods (POD7-13, POD14-20, POD21-27, and POD 28-34) and considered as single time points. OPN levels were determined in duplicate via ELISA and the results reported as mean ±SD. The paired t-test was used for analysis (significance, p<0.008 post Bonferroni correction).

Results: A total of 101 CRC patients (63% colon, 37% rectal) met the study criteria (51 male/49 female, mean age 65.2±13.3 years). Mean incision length was 7.7±3.3 cm; operative time was 288.8± 118.3 min and LOS was 6.6±3.9 days. The final cancer stage breakdown follows; I (n=26), II (n=37), III (n=34) and IV (n=4). The mean PreOp OPN level was 89.2±36.8 (ng/ml) for the entire group. Significantly elevated (p<0.001) mean plasma levels were detected on POD1 (198.0 ±67.4; n=101), POD 3 (186.0±76, n=101), POD7-13 (154.1±70.2, n=70), POD14-20 (146.7±53.4, n=32), and POD 21-27 (123.0±56.9, n=25). There was no significant difference noted when the POD 27-34 and PreOp results.

Conclusion: Plasma OPN levels are significantly elevated over baseline for a month after MICR for CRC. The increase in OPN levels early in the first week after MICR may be related to the acute inflammatory response that follows surgery. The persistent elevation noted during weeks 2-4, however, may be a systemic manifestation of wound healing in which OPN plays a role. This elevation, together with similar post MICR persistent elevations in levels of VEGF, ANG2, sVCAM, etc, may promote angiogenesis in residual tumor deposits early after MICR. Further studies are warranted.

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