Xiaozhi Zhang

Primary myoepithelial carcinoma of palate

ObjectivesThe aim of this study was to present a rare neoplasm, Primary myoepithelial carcinoma arising from the palate, and to review its diagnostic criteria, pathologic and clinical characteristics, treatment options and prognosis.Clinical Presentation and InterventionMyoepitheliomas are tumors arising from myoepithelial cells mainly or exclusively. Myoepitheliomas mostly occur in salivary glands, as well as in breast, skin, and lung. Case of myoepitheliomas in palate has rarely been reported. Myoepithelial carcinoma is malignant counterpart of myoepitheliomas. Adenomyoepithelioma is also a different disease from myoepitheliaomas. Immunohistochemically, tumor cells of myoepithelial carcinoma express not only epithelial markers such as cytokeratin, epithelial membrane antigen (EMA), but also markers of smooth muscle origin such as calponin. The immunohistochemical criteria of myoepithelial differentiation are double positive for both cytokeratins and one or more myoepithelial immunomarkers (i.e., S-100 protein, calponin, p63, GFAP, maspin, and actins). Myoepithelial carcinomas of salivary and breast demonstrate copy number gains and gene deletion. The overall prognosis of myoepithelial carcinoma is poor. There is rarely recurrence or metastasis in benign myoepithelial tumors. Complete excision with tumor-free margin is always the preferred treatment, while local radiation therapy and chemotherapy are suggestive treatment options. Here, a rare case of myoepithelial carcinoma arising from the palate has been described and discussed for the treatment and outcome. Pathological and clinical characters of myoepitheliomas are also compared and discussed.ConclusionThe case report serves to increase awareness and improve the index of diagnosis and treatment of myoepitheliomas.

Epigenetic Interventions Increase the Radiation Sensitivity of Cancer Cells

Epigenetic changes including DNA methylation, histone modifications, chromatin remodeling and microRNAs play critical roles in tumorigenesis and tumor development. Reversal of epigenetic changes sensitizes some tumor cells to radiation. DNMT-I enhances the response of tumor cells to radiotherapy. AZA demethylated promoters of genes related to ionizing radiation response, such as p16 and hMLH1. The genes expression of the p53, RASSF1, and DAPK gene families was increased by 5-aza-CdR, which induces G2-M phase arrest and increased apoptosis. HDAC-I has both anti-tumor activity and radiation sensitization activity. HDAC-I disrupts both DNA damage sensing and repair processes: HDAC-I disrupts the association between HDAC enzyme and DNA sensor proteins 53BP1 and ATM. HDAC-I changes the acetylation status of both proteins involved in homologous recombination (HR) repair pathway which include BRCA1, Rad51, and Rad50, and proteins involved in non-homologous end joining (NHEJ) repair pathway which include Ku70, and DNA-PK. HDACs are also implicated as essential components in the DNA repair process itself. Besides the radiosensitizing mechanism of intervention of DNA repair, other possible mechanisms including cell cycle redistribution, acetylation of Hsp90, increased apoptosis, and decreased survival signals are also suggested. Some miRNAs also regulate the radiosensitivity of tumor cells. Inhibition of miR-34 expression or function, downregulation of miR-155, upregulation of miR-18a, Overexpression let-7g or knocking down LIN28B, and ectopically overexpressed miR-10 in cells with low endogenous miR-101 level increase the response of cells to irradiation. For radiation-resistant cancer cells, miR-7 sensitizes the radiation for cells which activated EGFR-PI3K-AKT signaling pathway.

Tumor markers for early detection of ovarian cancer.

The overall mortality rate for ovarian cancer is 75%, but when diagnosed at stage I, 90% of patients can be cured. Strategies for early detection require high sensitivity (>75%) and extremely high specificity (99.6%) to attain a positive predictive value of at least 10%. When functioning alone, conventional markers fall short of this required sensitivity or specificity. Greater specificity can be achieved by combining multiple markers. Meanwhile, technological developments offer the potential identification of new candidate markers. Panels of new markers have been discovered with improved sensitivity and specificity for early-stage detection, but these require prospective validation. Through empirical development of: biotechnology (including monoclonal antibodies, gene expression, cloning of gene families and proteomics); statistical methods; and guidelines from specialized institutions, more candidate markers might be discovered and validated with systematic, efficient and cost-effective screenings.

HDAC as a Therapeutic Target for Treatment of Endometrial Cancers

Accumulating evidence suggested that epigenetic changes such as promoter-specific DNA hypermethylation and histone deacetylation cause tumor suppressor gene silencing and contribute to malignant transformation. Treatment of cancer cells with HDAC inhibitors can reactivate the expression of silenced genes, block the cell cycle, and induce cell apoptosis. In vitro experiments in cancer cell cultures and in vivo studies using mouse xynograft model have shown that HDAC inhibitors deliver potent anti-cancer effects. Clinical trials have led to approval of SAHA (Vorinostat) for treatment of lymphoma. Endometrial cancer (EC) is the most frequent malignancy in womens reproductive tract. EC is known for extensive epigenetic alterations, including overexpression of HDAC and DNMT enzymes, and the frequent epigenetic silencing of DNA repair genes such as MLH1, tumor suppressor genes PTEN, and progesterone receptor, which suggests a potentially high sensitivity of this type of cancer to HDAC inhibitors. Indeed, studies from many laboratories using various models have shown that HDAC inhibitors are promising chemotherapy reagents for endometrial cancers. This review summarizes the results from these studies, with an emphasis to provide an update on the new findings from new drugs. Background information on HDAC expression in EC, and features of HDAC inhibitors are presented based on their relevance to our focused topic. The combined application of HDAC inhibitors with radiation therapy and other conventional therapeutic reagents are also discussed.

GPER in CAFs regulates hypoxia-driven breast cancer invasion in a CTGF-dependent manner

Recent advances indicate that cancer‑associated fibroblasts (CAFs) play a key role in cancer progression by contributing to invasion, metastasis and angiogenesis. Solid tumors often experience low oxygen tension environments, which induce gene expression changes and biological features leading to poor outcomes. The G-protein estrogen receptor (GPER) exhibits a stimulatory role in diverse types of cancer cells and in CAFs under hypoxic conditions. We investigated the role of CAFs and hypoxia in breast cancer aggressiveness, and examined the effect of GPER in CAFs on hypoxia-driven breast cancer progression. The results showed that hypoxia upregulated HIF-1α, GPER and α-SMA expression in CAFs, and induced the secretion of Interleukin-6 (IL-6), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) in CAFs. However, GPER silencing abrogated the above hypoxia-driven cytokine expression in CAFs. Moreover, knockdown of GPER in CAFs suppressed breast cancer cell invasion induced by CAF conditioned media (CM). Furthermore, GPER silencing in CAFs inhibited hypoxia-increased CTGF expression in CAFs and breast cancer cells cultured with CM from CAFs under hypoxic conditions. In addition, CTGF is responsible for the observed effects of GPER on CAFs activation and breast cancer invasion. Our findings further extend the molecular mechanisms through which the tumor microenvironment may contribute to cancer progression.

Lysophosphatidic Acid Inhibits Apoptosis Induced by Cisplatin in Cervical Cancer Cells

Cervical cancer is the second most common cause of cancer death in women worldwide. Lysophosphatidic acid (LPA) level has been found significantly increased in the serum of patients with ovarian, cervical, and colon cancers. LPA level in cervical cancer patients is significantly higher than in healthy controls. LPA receptors were found highly expressed in cervical cancer cells, suggesting LPA may play a role in the development of cervical cancer. The aim of this study is to investigate the effect of LPA on the apoptosis induced by cisplatin (DDP) in cervical cancer cell line and the underlying changes in signaling pathways. Our study found that cisplatin induced apoptosis of Hela cell through inhibiting expression of Bcl-2, upregulating the expression of Bax, Fas-L, and the enzyme activity of caspase-3 (p < 0.05); LPA significantly provided protection against the apoptosis induced by cisplatin by inhibiting the above alterations in apoptotic factor caused by cisplatin (p < 0.05). Moreover, PI3K/AKT pathway was found to be important for the LPA antiapoptosis effect, and administration of PI3K/AKT partially reversed the LPA-mediated protection against cisplatin-induced apoptosis (p < 0.05). These findings have shed new lights on the LPA bioactivity in cervical cancer cells and pointed to a possible sensitization scheme through combined administration of PI3K inhibitor and cisplatin for better treatment of cervical cancer patients, especially those with elevated LPA levels.

Primary adenomyoepithelioma of tonsil

We present a case of adenomyoepithlioma (AME) arising from the tonsil. AME is an uncommon tumor that typically arises in breast, but rarely found in salivary glands, lung, and skin. Its biological features have not been thoroughly characterized. Here we describe a primary AME originating from the tonsil. The pathologic changes were characterized by hypercellularity, the dominance of both epithelial and myoepithelial cells. Malignancy was evidenced by the presence of a high mitotic rate and invasive growth. The epithelial cells express high levels of cytokeratin and epithelial membrane antigen (EMA). The myoepithelial cells show positive staining for calponin, p63, vimentin, and S-100. A thorough review of the literature indicates that this is likely the first reported case of AME from the tonsil. Following descriptions of the diagnosis, treatment, and prognosis of this specific case, pathologic and clinical characteristics of AME from other tissues are also compiled and discussed.

A20 enhances the radiosensitivity of hepatocellular carcinoma cells to 60 Co-γ ionizing radiation

The radioresistance of hepatocellular carcinoma (HCC) cells is a critical obstacle for effectively applying radiotherapy (RT) in HCC treatment. NF-κB, an important transcription factor, can influence critical cell fate decisions by promoting cell survival or anti-apoptosis in response to cell-stress, e.g. chemotherapies or ionizing radiation (IR). A20, also named as tumor necrosis factor α induced protein 3 (TNFAIP3), is a dominant negative regulator of NF-κB pathway and its functions in HCC are largely unknown. The present work aimed to reveal the role of A20 plays in affecting the radiosensitivity of HCC cells. Higher expression of A20 was detected in hepatic non-tumor cell line or clinical specimens compared with HCC cell lines or clinical specimens. A20 decreased the expression of proteins mediating cellular stress/injury response or epithelial-mesenchymal transition (EMT) process. Overexpression of A20 via adenovirus enhanced the effect of 60Co-γ ionizing radiation (IR) on HCC cells’ injury, e.g. G2/M arrest or DNA double strands break (DSB). Moreover, A20 also enhanced the in vitro or in vivo survival inhibiting of HCC cells induced by IR. These results reveal the roles of A20 in HCC radiosensitization and overexpression of A20 would be a novel strategy for HCC radiotherapy.

Analysis of the characteristics and prognosis of advanced non-small-cell lung cancer in older patients

Objective Lung cancer is still the leading cause of cancer-related deaths worldwide. However, most elderly patients with advanced non-small-cell lung cancer (NSCLC) have been undertreated and the outcome related to age is controversial. A retrospective analysis was conducted for advanced NSCLC in order to investigate the characteristics and prognosis of older patients. Methods Medical records were collected from 165 patients with NSCLC (stages IIIA–IIIB) who had been treated with concurrent chemoradiotherapy (CRT) or radiotherapy from January 2009 to January 2011. The cases were divided into two age groups 1) patients ≥70 years old; 2) patients <70 years old. There were 73 patients in group I, 92 in group II. Patient characteristics, treatment toxicities, and prognosis were evaluated. Results Of the 165 patients analyzed, 34 patients (34/73) in group I received concurrent CRT while 47 (47/92) in group II completed that treatment. No significant difference was observed in the reason for patients who discontinued CRT in two groups (P>0.05). In the patients with adenocarcinoma, more cases were found in group II than that in group I; the more squamous cell carcinoma and the more smokers with squamous cell carcinoma were seen in older group (P<0.05). With a median follow-up of 20.5 months, the 1-year survival for group I and II were 49.3% and 40.2% respectively (P=0.243). Two-year survival for the two groups was 20.5% and 16.3% (P=0.483); 3-year survival was 9.6% and 9.8% (P=0.967). There was no significant difference between two groups statistically in survival by univariate analysis (P>0.05). The therapy-related toxicities in group I seem to be similar to the group II (P>0.05). Conclusion More adenocarcinoma patients were found in youthful lung cancer and the more smokers with squamous cell carcinoma were seen in older group. Age is not the important factor for the selection and allocation of treatment in advanced NSCLC. The same prognosis and toxicities had been shown in older and young. Age may not be an independent increased risk of death in advanced NSCLC.

Effect of sinomenine hydrochloride on radiosensitivity of esophageal squamous cell carcinoma cells

Radiation therapy is one of the most important treatments for unresectable and locally advanced esophageal squamous cell carcinoma (ESCC), however, the response to radiotherapy is sometimes limited by the development of radioresistance. Sinomenine hydrochloride (SH) has anticancer activity, but its effect on the radiosensitivity of ESCC is unclear. We determined the effect of SH on the radiosensitivity of ESCC cells and elucidated its potential radiosensitization mechanisms in vitro and in vivo. ESCC cells were subjected to SH and radiation, both separately and in combination. Untreated cells served as controls. The CCK-8 assay was used to evaluate cell proliferation, and the clonogenic assay to estimate radiosensitization. Flow cytometry was used to investigate cell cycle phases and cell apoptosis. Bcl-2, Bax, cyclin B1, CDK1, Ku86, Ku70, and Rad51 expression was evaluated using western blotting. In vivo, tumor xenografts were created using BALB/c nude mice. Tumor-growth inhibition was recorded, and Ki-67 and Bax expression in the tumor tissues was assessed using immunohistochemistry. SH inhibited ESCC cell growth and markedly increased their radiosensitivity by inducing G2/M phase arrest. SH combined with radiation therapy significantly increased ESCC cell apoptosis. The molecular mechanism by which SH enhanced radiosensitivity of ESCC cells was related to Bcl-2, cyclin B1, CDK1, Ku86, Ku70, and Rad51 downregulation and Bax protein expression upregulation. SH combined with radiation considerably delayed the growth of tumor xenografts in vivo. Immunohistochemical analysis showed that in the SH combined with radiation group, the expression of Bax was significantly higher while that of Ki-67 was lower than the expressions in the control groups. Taken together, our findings showed that SH could improve the sensitivity of radiation in ESCC cells by inducing G2/M phase arrest, promoting radiation-induced apoptosis and inhibiting DSB-repair pathways. SH appears to be a prospective radiosensitizer for improving the efficacy of radiotherapy for ESCC.