Decreased number and reduced NKG2D expression of Vδ1 γδ T cells are involved in the impaired function of Vδ1 γδ T cells in the tissue of gastric cancer

Background

In cancer patients, impaired function of immune cells—such as CD8⁺ T cells, NK cells, and dendritic cells—reportedly results in tumor progression. Although γδ T cells also play a critical role in tumor defense, their function remains unclear in cancer patients.

Methods

The frequency and function of γδ T cells in peripheral blood, normal gastric mucosa, and cancer tissue were evaluated by multicolor flow cytometry. We also determined NKG2D expression on γδ T cells in gastric cancer patients.

Results

The frequency of Vδ1 γδ T cells in gastric cancer tissue is significantly lower than in normal gastric mucosa; however, differences in the frequencies of Vδ2 and Vγ9 γδ T cells between normal gastric mucosa and gastric cancer tissue were not statistically significant. The Vδ1 γδ T cells from gastric cancer tissue produce significantly less IFN-γ than those from normal gastric mucosa do. Expression of NKG2D on Vδ1 γδ T cells from gastric cancer tissue was significantly lower than in normal gastric mucosa. We also found a significant correlation between NKG2D expression and IFN-γ production of Vδ1 γδ T cells in gastric cancer tissue.

Conclusion

Vδ1 γδ T cells show decreased frequency and impaired function in gastric cancer tissue, for which decreased NKG2D expression might be one of the mechanisms. Modalities specifically targeting NKG2D in Vδ1 γδ T cells may provide a breakthrough treatment for gastric cancer patients.     

Potent antitumor activity of zoledronic acid-induced Vγ9Vδ2 T cells against primary effusion lymphoma

Primary effusion lymphoma (PEL) is a subtype of aggressive and resistant non-Hodgkin lymphoma that occurs predominantly in patients with advanced AIDS. In this study, we examined the antitumor activity of zoledronic acid (Zol)-induced Vγ9Vδ2 T cells against PEL cells in vitro and in vivo. Vγ9Vδ2 T cells recognized endogenous mevalonate metabolites and MICA/B of PEL cell lines, inducing cytotoxicity via granule exocytosis and TRAIL-mediated pathway. Vγ9Vδ2 T cells suppressed the development of PEL cells and existed in a PEL xenograft mouse model. These results show that immunotherapy with Zol-induced Vγ9Vδ2 T cells could demonstrate an efficient strategy for PEL.     

Identification of ABCG2⁺ cells in nasopharyngeal carcinoma cells

Tumor stem cells are a small subset of tumor cells with the ability of self-renewal and differentiation and are regarded as a cause of tumor growth and recurrence. Previously we have shown that stem-like label-retaining cells (LRCs) can be detected in nasopharynx, tongue, esophagus and xenograft tumors formed by nasopharyngeal carcinoma (NPC) cell lines (5-8F, 6-10B and TMNE). The present study aimed to identify ABCG2? cells in 5-8F NPC cells and compare their tumorigenic potential with ABCG2? cells, expecting that we can obtain insight into the mechanism of the differential phenotypes of ABCG2? and ABCG2? cells. By using magnetic cell sorting (MACS) method, we isolated ABCG2? cells and ABCG2? cells from 5-8F cells. Among these two subpopulations and unsorted 5-8F cells, the rate of ABCG2? cells at G1 phase was highest, while the rate of ABCG2? cells at S phase was highest, indicating that ABCG2? cells were mostly quiescent. However, ABCG2? cells showed lower cloning efficiency and tumorigenicity than ABCG2? cells. We also used Affymetrix U133 plus 2.0 human whole genome expression chip to identify the gene expression profile of ABCG2? and ABCG2? cells and found that both subpopulations expressed some stem cell associated genes, e.g., PSCA, ABCG2 and ALPI were expressed in ABCG2? cells, and K19, integrin α6, integrin β4, CD44 and K14 were expressed in ABCG2? cells, suggesting there were stem cells in both ABCG2? and ABCG2? cells. Our data demonstrated that there exist ABCG2? cells in NPC cells, but ABCG2 alone is not sufficient for isolating cancer stem cells in 5-8F NPC cells.     

Recovery of anoikis in Src-transformed cells and human breast carcinoma cells by restoration of the SIRP α1/SHP-2 signaling system

Src kinase dysregulation contributes to cancer progression but mechanistic understanding for this contribution remains incomplete. Signal regulatory protein α1 (SIRPα1) is a tumor suppressor that is constitutively suppressed in v-Src-transformed cells, where restoration of SIRPα1 expression inhibits anchorage-independent growth. In this study, we investigated the role of the protein tyrosine phosphatase-2 (SHP-2) in SIRPα1 activity. SHP-2 suppression resulted in a blockade of SIRPα1-mediated inhibition of anchorage-independent growth. Notably, we found that SIRPα1 did not act in v-Src-transformed cells by triggering cell growth arrest but by eliciting a suspension-selective apoptosis (anoikis), and that SHP-2 was required for this effect. Furthermore, we found that SHP-2 was crucial for recovery of stress fiber and focal contact formation by SIRPα1 in v-Src-transformed cells. Finally, we found that SIRPα1/SHP-2 signaling regulates anoikis in human breast carcinoma cells with activated c-Src. Taken together, our findings define SHP-2 as an essential component of tumor suppression and anoikis mediated by SIRPα1 in human breast carcinoma cells as well as in v-Src-transformed cells.     

Cancer stem-like cells in human prostate carcinoma cells DU145: the seeds of the cell line?

The aim of this study is to investigate cancer stem cells and their markers in the prostate cancer cell line Du145. Different populations of cells were isolated from Du145. The clones formed by CD44+ integrinalpha(2)beta(1)+CD133+ cells are remarkably different morphologically and quantitatively from those formed by integrinalpha(2)beta(1)(-/low)CD133(-) cells. CD133(+) cells have the capacity for self renewal, extensive differentiation potential, and high proliferative and tumorigenic potential. CD34+ and CD117+ cells have no stem cell properties. Expression levels of c-myc and beta-catenin were elevated and bax was down regulated in CD44+ integrinalpha(2)beta(1)+CD133+ cells. In summary, CD44, integrinalpha(2)beta(1) and CD133 could be the cancer stem cell makers for the Du145 cell line. CD133+ cells differed significantly from CD44+ integrinalpha(2)beta(1)(-/low)CD133- cells and the total population in clone generation, genes expression, differentiation, proliferative and tumorigenic potential.     

Stem cells as vehicles for the treatment of brain cancer

Stem cell therapy represents a promising new therapeutic modality for infiltrative gliomas. The promise of this emerging technology centers on the potent migratory tropism exhibited by stem cells for disseminated foci of intracranial pathologic findings. This important characteristic, which has been validated in a wide set of preclinical studies, forms a foundation for the use of transplanted stem cell populations as vehicles for the delivery of tumor-toxic molecules to sites of intracranial tumor. Nevertheless, although experimental models using this technique to target brain tumors have shown encouraging results,[第一段]     

How does DNA methylation mark the fate of cells?

Since every cell of a multicellular organism contains the same genome, it is intriguing to understand why genetically homogenous cells are different from each other and what controls this. Several observations indicate that DNA methylation has an essential regulatory function in mammalian development, which is to establish the correct pattern of gene expression, and that DNA methylation pattern is tightly correlated with chromatin structure. Various physiological processes are controlled by specific DNA methylation patterns including genomic imprinting, inactivation of the X chromosome, regulation of tissue-specific gene expression and repression of transposons. Moreover, aberrant methylation could confer a selective advantage to cells, leading to cancerous growth. In this review we focus on the epigenetic molecular mechanisms during normal development and discuss how DNA methylation could affect the expression of genes leading to cancer transformation.     

Inhibition of the growth of cultured human meningioma cells by recombinant interferon-α

In this paper the results of investigations on the effect of interferon-α (IFN-α) on the growth of meningioma cells in culture is reported. A consecutive series of six meningiomas and one meningioma/neurofibroma derived from a patient with neurofibromatosis type 2 was investigated and it was found that the growth of all seven tumours in response to mitotic stimuli (fetal bovine serum or epidermal growth factor) is strongly inhibited by IFN-α. Maximal response varied between 100% and 70% inhibition of the incorporation of tritiated thymidine. In some cases an inhibitory response was obtained already at very low doses (≤10 U of IFN-α per ml). These results indicate that further clinical investigation of the application of IFN-α to the treatment of meningioma is warranted.     

Thrombomodulin mediates the migration of cervical cancer cells through the regulation of epithelial–mesenchymal transition biomarkers

Thrombomodulin (TM) has been shown to regulate many physiological and pathological processes, including inflammation, thrombosis, and tumor progression. TM is also a natural anticoagulant that maintains circulatory homeostasis in endothelial cells. However, little is known regarding the role of TM in the progression and metastasis of cervical cancer. TM-specific RNA interference and a cDNA expression vector were used to manipulate TM expression in cervical cancer cells. Cell growth and cell migration were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, transwell migration assays, and a biosensor system. TM silencing did not affect the growth rate of the cells. However, cell migration was dramatically enhanced after silencing of TM in HeLa cells. The overexpression of TM in cervical cancer cells only slightly influenced their proliferative capacity. After overexpression of TM in HeLa cells, their migratory capability was suppressed. Furthermore, we found that the decreased expression of E-cadherin and increase of zeb-1 and snail expression in TM-silenced cells which may be correlated with the results of knocking-down TM increases the migratory ability in this study. Our results demonstrate that TM may slightly regulate the growth but played the important role in the migratory ability of cervical cancer cells, suggesting that TM could potentially serve as a novel prognostic and therapeutic target in cervical cancer.     

Blocking the formation of radiation–induced breast cancer stem cells

The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu²⁺). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu²⁺ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer.     

Stem cells of ependymoma

Ependymomas are tumours that arise throughout the central nervous system. Little is known regarding the aberrant cellular and molecular processes that generate these tumours.[第一段]     

Preferential replication of Sézary cells in the epidermis.

Skin biopsies from three patients with Sézary Syndrome have been labeled in vitro with H-3Thymidine. Labeled cells have been counted in semithin Epon embedded sections and characterized by electron microscopic autoradiography. The ratio of labeled Sézary cells to total lymphocytes was two to four times higher in the epidermis than in the dermis. It is concluded that Sézary cells replicate in the skin and that epidermal cells seem to possess new blastogenic properties in Sézary Syndrome.     

Inhibitors of Bcl-2 sensitize tumor cells to immune attack

T cells and NKT cells are the major effector lymphocytes in the immune attack against tumor cells.The cytotoxic effect is achieved by inducing apoptosis of tumor target cells.The cytotoxic activity is mediated by perforin/ granzyme-B,Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand(TRAIL).Since killing by these mechanisms is blocked by the anti-apoptotic oncoprotein Bcl-2,which is frequently over-expressed by tumor