Increased plasma transforming growth factor beta1 (TGFβ1) level in lung cancer patients may be due to the loss of mannose 6-phosphate / insulin like growth factor 2 receptor (M6P/IGF2R)

Purpose/Objective: Increased plasma TGFβ1 have been reported in patients with hepatocellular carcinoma, lung cancer, cervical carcinoma, Hodgkin's disease, breast cancer and prostate cancer. M6P/IGF2R, a tumor suppresser gene in hepatocellular carcinoma and breast cancer, is involved in the bioactivation process of TGFβ. The purpose of this study was to investigate the role of the M6P/IGF2R gene in regulation of the plasma TGFβ1 level. Material and Methods: Archival pathology specimens were obtained on 20 patients with newly diagnosed, untreated lung carcinoma on whom banked plasma obtained prior to treatment was also available. Microdissection of tumor and surrounding normal tissue from 6 micron paraffin embedded histological sections was performed. Using the polymerase chain reaction, we utilized two polymorphisms in the 3' untranslated region of the M6P/IGF2R to screen for loss of heterozygosity (LOH). Plasma TGFβ1 levels were measured using acid-ethanol extraction and an ELISA. TGFβ and M6P/IGF2R protein expressions were estimated by Immunohistochemical staining technique. Chi square test was applied for the statistic analysis. Results: Of the 20 patients, 16 were informative (heterozygous) and the remaining 4 patients were not. The correlation between LOH at the M6P/IGF2R locus and an elevation in plasma TGFβ1 level is shown in the table. Eighty-nine percent ((8(9))) OF patients with LOH had increased TGFβ1 levels, while only fourteen percent ((1(7))) of patients without LOH had increased TGFβ1 levels. The incidence of increased TGFβ1 levels in patients with LOH is significantly higher than patients without LOH (P<0.005). A decrease or loss of M6P/IGF2R expression in the malignant cell accompanied by an increased TGFβ1 expression in interstitial matrix and tumor stroma were found in LOH samples. Conclusions: Loss of the M6P/IGF2R resulting in an absence of the growth inhibitory response in malignant cells to TGFβ is a possible mechanism for increased local TGFβ expression in tumor extracellular matrix and stroma. This may be responsible for an increased TGFβ1 level in the circulation. Thus, abnormal function of M6P/IGF2R may be the cause for the increased plasma TGFβ1 in lung cancer patients