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Plasma Levels of Progranulin, a Tumorgenic Protein, Are Persistently Elevated During the First Month After Minimally Invasive Colorectal Cancer Resection
H M C Shantha Kumara*1, Hiromichi Miyagaki1,2, Xiaohong Yan1, Linda Njoh1, Vesna Cekic1, Nipa D. Gandhi1, Richard L. Whelan1
1Department of Surgery, Colon and Rectal Division, Mount Sinai Roosevelt Hospital, New York, NY; 2Department of Surgery, Saiseikai Senri Hospital 1-1-6, Tsukumodai, Suita, Osaka, Japan 565-0862, Suita,, Japan
Introduction: Progranulin (PGRN), also known as Precursor Cell-Derived Growth Factor (PCDGF), is a ubiquitously expressed and secreted glycoprotein. PGRN is involved in the regulation of cellular proliferation, differentiation and pathological processes. As a growth factor PGRN activates both the PI3k and ERK pathways, and promotes cyclin D1 and cyclin B expression which supports the proliferation and survival of mesenchymal and epithelial origin cells. PGRN overexpression has been noted in breast, ovarian, and renal cancers, among others. PGRN also stimulates VEGF expression in breast cancer cells in vitro. Application of PGRN to a wound stimulates inflammation, fibroblast accumulation and new blood vessel formation, each of which is essential to wound healing. Surgery’s impact on PGRN levels is unknown. This study’s purpose was to measure plasma PGRN levels before and during the first month after minimally invasive colorectal resection (MICR) for colorectal cancer resection (CRC).
Method: CRC patients enrolled in an IRB approved data/plasma bank who underwent MICR for whom adequate plasma samples were available were studied. Clinical and pathologic data were reviewed. Blood samples were routinely collected preoperatively (preop) and at a variety of postoperative (postop) time points. Plasma was isolated and stored at -80°C. Late samples were bundled into 7 day blocks and considered as single time points. PGRN levels (pg/ml) were determined in duplicate via ELISA and reported as mean± SD. The paired t-test was used for statistical analysis (significance p<0.008 after Bonferroni correction).
Results: Preop and 1 or more late postop plasma sample were available for 93 MICR CRC patients (colon 73%; rectal 27%; 50 male /43 female, mean age 66.3± 13.2 years). The mean incision length was 7.8±3.6 cm and mean length of stay was 6.7± 4.1days. The final cancer stage breakdown was; Stage I, 37%, Stage II, 27%, stage III, 32% and stage IV, 4%. The mean preop PGRN level was 53.3± 12.5 pg/ml. When compared to preop levels, significantly elevated (p<0.0001) mean levels (pg/ml) were noted on postop day (POD) 1 (65.8± 15.2; n=92), POD 3 (73.0±17.8,n=85), POD7-13 (67.1±16.7, n=68), and POD14-20 (69.9±13.1,n=26), POD 21-27(71.2±14.8, n=20) and on POD 28-34 (72.8± 17.1, n=22; p=0.0003).
Conclusion: Plasma PGRN levels were significantly elevated over baseline for 1 month after MICR for CRC. The early increase after surgery may be due to the short lived acute inflammatory response. The elevation noted during weeks 2 and 4 may be related to wound healing since PGRN stimulates fibroblast accumulation and promotes angiogenesis in wounds. Elevated levels of PGRN may stimulate angiogenesis in residual tumor deposits after surgery. Further investigation is warranted.
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