Plasma levels of Keratinocyte Growth Factor, a proangiogenic protein, are significantly elevated for 3 weeks after minimally invasive colorectal resection (MICR) for cancer

Hmc Shantha Kumara, PhD1, Hiromichi Miyagaki, MDPhD2, David Giata, BS1, Xiaohong Yan, PhD1, Linda Njoh, PhD1, Cekic Vesna, RN1, Melissa M Alvarez-Downing, MD1, Richard L Whelan, MD1. 1Department of Surgery, Mount Sinai Roosevelt Hospital, New York, NY 10019, USA, 2Department of Gastroenterological surgery,Osaka University,Osaka, 565-0871 Japan.

Introduction: Human Keratinocyte Growth Factor (KGF), also known as Fibroblast Growth Factor (FGF) 7, is a single chain, heparin-binding FGF family protein. KGF is produced by cells of mesenchymal origin yet has its effect on epithelial cell subpopulations, keratinocytes for example, which express the KGF cell surface receptor (KGF-R) which has tyrosine kinase activity. It is thought to be a paracrine promoter of epithelial cell proliferation and differentiation. KGF also plays a role in the epithelialization phase of wound healing during which keratinocytes line the wound. KGF expression has been noted in colorectal cancers (CRC) and is thought to support tumor cell proliferation and invasion. Overexpression of endogenous KGF has been noted in well differentiated CRC and is associated with increased VEGF-A production. MICR has been associated with persistent proangiogenic plasma protein changes that may stimulate the growth of residual cancer after surgery. Surgery’s impact on KGF levels is unknown. This study’s purpose was to evaluate plasma KGF levels during the first month after MICR for CRC.

Method: CRC patients enrolled in an IRB approved data/plasma bank who underwent elective MICR for whom plasma samples were available were studied. Clinical and pathologic data were reviewed. Blood samples were collected preoperatively (preop) and at a variety of post-operative (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. KGF 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, at least, 1 late postop plasma sample were available for 80 MICR CRC patients (colon 61%; rectal 39%; 37 male /43 female, mean age 65.8± 13.3 years). The mean incision length was 6.5±2.6 cm, mean operative time 295.0± 129.9min, and mean length of stay was 6.5±2.6 days. The final cancer staging breakdown was; Stage I, 29%, Stage II, 34%, stage III, 32% and stage IV, 5%. The mean preop KGF level was 17.7± 8.3 pg/ml. When compared to preop levels, significantly elevated (p<0.0001) mean levels (pg/ml) were noted on postoperative day (POD) 1 (24.7± 12.8; n=80), POD 3 (27.3±18.3, n=76), POD7-13 (23.4±12.6, n=50), and POD14-20(23.6±12.1, n=33). No significant difference in plasma KGF levels were noted for the POD 21-27 (19.2 ±6.6, n=15, p=.03) and POD28-34 (vs. PreOp, p=0.3) time blocks.

Conclusion: Plasma KGF levels were significantly elevated over baseline for 3 weeks after MICR for CRC. The early rise after surgery may be due to the short lived acute inflammatory response, however, the elevation noted during weeks 2 and 3 may is more likely related to wound healing in which KGF plays a role. The KGF increase, together with similar persistent post MICR elevations in blood levels of VEGF, PlGF, ANG2, etc. may stimulate angiogenesis in residual tumor deposits after surgery. Further investigation is needed.

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