Intratumoral lactate dehydrogenase 5 (LDH5) protein expression is associated with expression of angiogenesis markers and hypoxia in patients with colorectal cancer (CRC)

Abstract

4107 Background: Recent clinical trials (CONFIRM 1 and CONFIRM 2) have shown that metastatic CRC patients (pts) with high serum lactate dehydrogenase (LDH) derive the greatest therapeutic benefit from PTK787/ZK 222584 (PTK/ZK). PTK/ZK is a novel, oral tyrosine kinase inhibitor (TKI), which blocks all known VEGF receptors (VEGFR). From previous studies, total LDH and isoenzyme LDH5 have been associated with tumor aggressiveness and hypoxia. In the present study, we tested whether CRC pts with high levels of tumor LDH5 have increased expression of proteins involved with hypoxia (hypoxia inducible factors [HIF1a and 2a], pyruvate dehydrokinase [PDHK]), increased vessel density (VD), angiogenesis (VEGFA; phosphorylated VEGFR2 [pKDR]), acidity (carbonic anhydrase 9 [CA9]), and others. Methods: Baseline sections from either primary or metastatic tumor sites from 42 pts of the CONFIRM 1 and 2 trials were analysed with immunohistochemistry utilizing an established nominal scoring system. The degree of association between the scores of protein expressed was estimated by the phi-coefficient (correlation coefficient) and assessed by means of p-values from pairwise Fisher’s exact test (two- sided). Results: Associations were observed between LDH5 and the following: pKDR (Phi=.53; p<.001), VEGF (Phi=.41; p=.006), HIF-1a (Phi=.56; p<.001), VD (Phi=.34; p=.052), and PDHK (Phi=.58; p=.014), respectively. HIF-1a associated with pKDR (Phi=.38; p=.027), VD (Phi=.34; p=.045), and VEGFA (Phi=.33; p=.067). VEGFA associated with PDHK (Phi=.52; p=.035). Conclusions: Our results demonstrate that mCRC patients with high level of intratumoral protein expression of LDH5 have elevated HIF-1a, pKDR, VEGFA, PDHK expression and VD. These results support the concept that tumor hypoxia and angiogenesis are associated and that elevated LDH protein expression may serve as a surrogate marker for activated HIF-1a pathway. No significant financial relationships to disclose.