Preliminary study of hypoxia markers in diffuse large B‑cell lymphoma

Abstract

While the association of hypoxia has been established in various types of solid cancers, little is known about its presence and existence in diffuse large B-cell lymphoma (DLBCL). The purpose of the present study was to evaluate the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGF-A) in DLBCL and to analyze the association of these factors with several clinical and pathological characteristics. The immunohistochemical protein expression of HIF-1α and VEGF-A was investigated in 34 de novo DLBCL tumor samples from January 2017 to December 2017 from the Department of Hematology/Medical Oncology and Anatomical Pathology at Dr Kariadi Hospital (Semarang, Indonesia). The present study revealed by using immunohistochemistry (IHC), that hypoxic markers were overexpressed (88.2% for both HIF-1α and VEGF-A) in the vast majority of patients with DLBCL. Only in 4 tumors, was HIF-1α expression normal, and interestingly VEGF-A was negative as well. There was a significant correlation in the intensity of staining of HIF-1α and VEGF-A using our custom scoring system in surgically resected tissues (r=0.475; P=0.005). Both HIF-1α and VEGF-A were also associated to serum LDH and tumor diameter. Collectively, HIF-1α and VEGF-A were predominantly expressed in the majority of DLBCL tumor cells. The findings of the present study indicate the existence of hypoxia in DLBCL tumors similar to numerous solid cancers, and thus warrants further investigation to clarify its role as a potential pathogenic or prognostic marker in this type of hematological cancer.

The expression of hypoxia inducible factor-1 alpha in diffuse large B-cell lymphoma (DLBCL) patients: a cross-sectional study in Indonesia

“…To the best of our knowledge, no studies have yet investigated the correlation between HIF-1α expression and serum VEGF levels in patients with DLBCL. In our previous preliminary research study, it was found that the expression of HIF-1α was positively correlated with the expression of VEGF in tissues 5 . The lower serum VEGF levels in the HIF-1α distribution greater than or equal to 40% group, compared to the HIF-1α distribution less than 40% group, may be due to the larger size of the lymphoma tumour being influenced by inflammation rather than angiogenesis 21 .…”

“…Secondly, the positive correlation between sIL-2R and VEGF, as well as between sIL-2R and tumour volume, suggests that the immune system may play a role in modulating tumour angiogenesis and growth in DLBCL. sIL-2R is a marker of T-cell activation and proliferation, and may reflect the distribution of immune infiltration and activation within the tumour microenvironment 5 , 18 .…”

“…The result of tissue oxygenation below the physiological level can disrupt the maintenance of normal cell function. Generally, pO2 levels below 10 mmHg will activate hypoxia inducible factor-1 (HIF-1) and other adaptive molecular pathways to maintain cellular function 4 , 5 . Hypoxia refers to a very low oxygen level, with oxygen levels between 5 and 10 mmHg 4 , 6 .…”