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Thymidine Kinase 1 and Thymidine Phosphorylase Expression in Non–Small-cell Lung Carcinoma in Relation to Angiogenesis and Proliferation

J. Scott Brockenbrough¹, Janice K. Morihara¹, Stephen E. Hawes, Joshua E. Stern, Janet S. Rasey, Linda W. Wiens, Qinghua Feng and Hubert Vesselle

Division of Nuclear Medicine, Department of Radiology (JSB,LWW,HV), Department of Pathology (JKM,JES,QF), Department of Epidemiology, School of Public Health and Community Medicine (SEH), and Department of Radiation Oncology (JSR), University of Washington School of Medicine, Seattle, Washington

Correspondence to: Hubert Vesselle, PhD, MD, Director, Division of Nuclear Medicine, Department of Radiology, University of Washington Medical Center, Box 357115, 1959 NE Pacific Street, Seattle, WA 98195-7115. E-mail: vesselle{at}u.washington.edu

The thymidine salvage pathway enzymes thymidine kinase 1 (TK1) and thymidine phosphorylase (TP) compete for thymidine as a substrate and catalyze opposing synthetic and catabolic reactions that have been implicated in the control of proliferation and angiogenesis, respectively. We investigated the relationship between the expression of TK1 and TP as they relate to proliferation (Ki-67 labeling index) and angiogenesis (Chalkley count of CD31-stained blood vessels) in a series of 110 non–small-cell lung cancer (NSCLC) tumors from patients prospectively enrolled in an imaging trial. TK1 and TP exhibited similar patterns of immunohistochemical distribution, in that each was found in both the nucleus and the cytoplasm of tumor cells. Each enzyme exhibited a significant positive correlation between its levels of nuclear and cytoplasmic expression. A significant positive correlation between TK1 expression and the Ki-67 labeling index (r = 0.53, p<0.001) was observed. TP was significantly positively correlated with Chalkley scoring of CD31 staining in high vs low Chalkley scoring samples (mean TP staining of 115.8 vs 79.9 scoring units, p<0.001), respectively. We did not observe a substantial inverse correlation between the TP and TK1 expression levels in the nuclear compartment (r = –0.17, p=0.08). Tumor size was not found to be associated with TK1, TP, Ki-67, or Chalkley score. These findings provide additional evidence for the role of thymidine metabolism in the complex interaction of proliferation and angiogenesis in NSCLC. (J Histochem Cytochem 57:1087–1097, 2009)

Key Words: thymidine kinase 1 • thymidine phosphorylase • NSCLC • angiogenesis • proliferation

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