Notch signaling defects in NK cells in patients with cancer.

Altered expressions of proto-oncogenes have been reported during normal lymphocytes mitogenesis and in T and B lymphocytes in patients with autoimmune diseases. We have recently demonstrated a significantly decreased expression of c-kit and c-Myc in NK cells isolated from patients with cancer, which might be related to the functional deficiency of NK cells in the tumor environment. Here, focusing on the regulatory mechanisms of this new clinical phenomenon, we determined expression of c-Myc, Notch1, Notch2, p-53, Cdk6, Rb and phosphorylated Rb in NK cells isolated from the healthy donors and cancer patients. The results of our study revealed a significant down-regulation of expression of Notch receptors and up-regulation of Cdk6 expression in NK cells in cancer, while no significant changes in the expression of p53 and Rb proteins were seen. These data revealed novel signaling pathways altered in NK cells in the tumor environment and support further investigation of the origin of deregulated expression of proto-oncogenes in NK cells patients with different types of cancer.

Abnormal Expression of c-Myc Oncogene in NK Cells in Patients with Cancer.

Natural killer (NK) cells have received a lot of attention in recent years for the roles they play in immunity and particularly in antitumor immune responses. Although defects in NK cell functions are recognized as important mechanisms for immune evasion of malignant cells, molecular pathways regulating NK cell dysfunction and exhaustion in cancer are largely unknown. Here we tested whether the c-myc proto-oncogene, known to promote cell proliferation, growth, differentiation, and apoptosis by regulating the expression of numerous target genes, may be involved in the mechanism of NK cell abnormalities in patients with lung and gastric cancer. Analysis of c-myc mRNA and protein expression in peripheral blood NK cells, mitogen-activated protein kinase (MAPK) activity, cell cycle, and cell longevity revealed a significantly decreased expression of c-myc mRNA and protein and mitotic arrest of NK cells in different phases of cell cycle. In addition, a significant decrease of NK cell death was also detected. These data allow the suggestion that defects of NK cell-mediated tumor surveillance may be associated with disturbed c-myc expression in NK cells in cancer patients. A better understanding of the mechanisms of NK cell dysfunction in cancer will help in the NK cell-mediated therapeutic eradication of primary and metastatic cancer cells and prolong patient survival.

Alterations of oncogenes expression in NK cells in patients with cancer.

INTRODUCTION: C-kit/SCF signaling plays a key role in regulating NK cell homeostasis, maturation, proliferation, and cytotoxicity. C-kit-deficiency in NK cells results in significant reduction of their number, suggesting an imperative role for c-kit signaling in NK cell biology. We have recently showed that human NK cells express not only c-kit-receptor, but also both membrane-bound and soluble forms of c-kit ligand-Stem cell factor. The goal of this study was to characterize the c-kit/SCF autocrine loop in peripheral blood NK cells obtained from patients with cancer. METHODS: Using Smart Flare and qRT-PCR, we have characterized expression of c-kit and two forms of SCF in patients' NK cells and correlated these results with the expression of c-myc and STAT3. RESULTS: Our results demonstrated that the expression of proto-oncogenes c-myc and c-kit was significantly decreased in NK cells from all cancer patients. Expression of membrane-bound SCF in NK cells correlated with the presence of remote metastases. CONCLUSIONS: We suggest that the abnormal signaling and expression of c-kit/SCF, c-myc, and STAT3 in NK cells is responsible for the defect in their cytolytic activity in cancer and these defects at the gene expression level may be the cause rather than the result of tumor progression.