Jinlu Ma

Antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing an alternative circulatory system

Antiangiogenesis therapy is one of the most promising approaches to cancer treatment. Its clinical success has come out but still too limited. Vascularization of tumor is a complex and heterogenous process. So far, it has been demonstrated that several additional mechanisms can provide the tumor with oxygen and nutrients. Moreover, it is now clear that vascularization of tumor does not necessarily depend on endothelial cells proliferation and sprouting of new capillaries. Vasculogenic mimicry (VM) as an alternative circulatory system, has been described in multiple malignant tumor types, and considered to be associated with a poor prognosis for the patient. VM serves as an adjunct to the existing vasculature system, thereby aiding tumor growth as well as contributing to the metastatic process. Moreover, hypoxia has been confirmed to promote some tumor cells to form vessel-like tubes in vitro and express genes associated with VM. Yet, the current antiangiogenesis strategies, which are directed mainly against the tumor endothelium and then cause hypoxia of tumor cells, have no effect on VM. Our central hypothesis is that when the endothelium-dependent vessels are inhibited by the effective angiogenesis inhibitors, the hypoxia of tumor cells caused by antiangiogenesis may increase VM compensatively which can replace the job of endothelium-dependent vessels to maintain the tumor blood supply and provide a convenient route of tumor metastasis. As a result, antiangiogenesis therapy might have the unintended effect of promoting tumor metastasis by increasing VM. Thus, treatment strategies that target the tumor microcirculation should not only target endothelium-dependent vessels, but also take VM into account in tumors presenting VM.

Serum SALL4 Is a Novel Prognosis Biomarker with Tumor Recurrence and Poor Survival of Patients in Hepatocellular Carcinoma

Aim. Sal-like protein 4 (SALL4), is reexpressed in tissues of a subgroup of HCC associated with poor prognosis. Reports of SALL4 serological levels linked to HCC patients are meager and unclear in the prognosis of this malignancy. Methods. Immunohistochemistry and optical microscopy protocols were used to examine the presence of SALL4 in liver tissues from the following patients: 38 HCC, 11 chronic hepatitis B virus (HBV), 13 liver cirrhosis, and 12 healthy controls. Additionally, enzyme-linked immunosorbent assay (ELISA) was used to measure the SALL4 levels in serum samples isolated from patients as follows: 127 with HCC, 27 with HBV, 24 with liver cirrhosis, and 23 normal controls. Results. Analysis of liver tissues sections from HCC patients (18 out 38; 47.4%) showed positive staining for SALL4 and its expression did no correlate with any of the clinicopathologic characteristics. HCC patients displayed higher levels (50.4%) of SALL4 protein in serum, compared with the three control groups. Moreover, SALL4 concentration reached the maximum level after one week after treatment and dropped quickly after one month. These HCC patients showing high SALL4 serum levels had poor prognosis, evidenced by both tumor recurrence and overall survival rate. Conclusions. High SALL4 serum levels are a novel biomarker in the prognosis of HCC patients.

Molecular Beacons: A Novel Optical Diagnostic Tool

As a result of the efforts of the Human Genome Project and the rise in demand for molecular diagnostic assays, the development and optimization of novel hybridization probes have focused on speed, reliability, and accuracy in the identification of nucleic acids. Molecular beacons (MBs) are single-stranded, fluorophore-labeled nucleic acid probes that are capable of generating a fluorescent signal in the presence of target, but are dark in the absence of target. Because of the high specificity and sensitivity characteristics, MBs have been used in variety of fields. In this review, MBs are introduced and discussed as diagnostic tools in four sections: several technologies of MBs will be illustrated primarily; the limitation of MBs next; the third part is new fashions of MBs; and the last one is to present the application of MBs in disease diagnosis.

Effect of socio-economic factors on delayed access to health care among Chinese cervical cancer patients with late rectal complications after radiotherapy

OBJECTIVES To determine the effect of socio-economic status (SES) on delayed access to medical treatment by Chinese cervical cancer patients who suffered from late rectal sequelae (LRS) after external beam radiation therapy (EBRT) and intracavitary brachytherapy. METHODS Patients diagnosed with LRS were interviewed for their SES, factors including age, residing district, religion, marital status, income, education, insurance and patient delay (the time interval from the onset of symptoms to the first medical consultation) and other factors such as weight, symptom duration and disease stage at diagnosis. RESULTS One hundred and twenty nine patients were interviewed. Seventy-one patients (55%) sought medical treatment within three months after the first symptom being recognized and fifty-eight patients (45%) delayed their medical treatment over 3 months. The study shows that age ≥ 55 (OR=12.1; 95% CI: 3.3-43.9), lower education (OR=4.6; 95% CI: 2.0-10.4 for women with primary school education or illiterate), low annual household income (OR=2.3; 95% CI: 1.2-5.1) and widow/divorce (OR=0.1; 95% CI: 0.01-0.07) were the high risk factors for delayed reporting. Patients with bleeding or bleeding plus other symptoms (61.2%) were more likely to seek treatment within three months, compared to patients with other symptoms only (38.8%) (p=0.002). Additionally, delayed reporting was found to be significantly associated with the late stage of late rectal sequelae (LRS) (p=0.000) and the patients with 55 years or older (p=0.000). CONCLUSIONS Delayed reporting and late-stage presentation of late rectal sequelae are more prevalent among Chinese cervical cancer patients with 55 years or older, low education, poor marital status, or poor financial status. Effective social support and educational programs should be implemented to encourage these patients to seek medical treatment as soon as possible.

Systemic delivery of lentivirus-mediated secretable TAT-apoptin eradicates hepatocellular carcinoma xenografts in nude mice

Apoptin, a chicken anemia virus-derived protein, has been shown to induce apoptosis in various human cancer cell lines, but not in normal cells, thus making it a candidate for the development of novel therapeutic strategies. To enable the efficient transduction of tumor cells with apoptin, we have developed a novel mammalian expression system for the secretion of apoptin in vitro. We have previously shown the efficient and tumor-specific killing of cells by adding a secretory signal peptide (SP) to the N terminus of transacting activator of transcription (TAT)-apoptin (SP-TAT-apoptin). In addition, our report showed the successful secretion of high levels of TAT-apoptin/GFP into the culture medium from HUVEC cells infected by lentivirus LV-SP-TAT-apoptin/GFP. To obtain sustained apoptin-induced tumor cell death in vivo, we injected the LV-SP-TAT-apoptin viruses via the tail vein for systemic delivery of the viruses; viruses expressing LV-SP-TAT-GFP were used as a negative control. Markedly, almost all the hepatocellular carcinoma xenograft tumors disappeared following the treatment while the xenografts that received the control LV-SP-TAT-GFP viruses continued to grow. Moreover, the animal studies presented in this paper demonstrate a low toxicity of SP-TAT-apoptin in vivo, confirming and extending the results of the in vitro studies. Taken together, our data strongly suggest that systemic delivery of lentivirus-mediated secretable TAT-apoptin is feasible to eradicate liver cancer in vivo.

The Intensity of Radiotherapy-Elicited Immune Response Is Associated with Esophageal Cancer Clearance

Radiation therapy is one of the standard therapeutic modalities for esophageal cancer, achieving its main antitumor efficacy through DNA damage. However, accumulating evidence shows that radiotherapy can substantially alter the tumor microenvironment, particularly with respect to its effects on immune cells. We hypothesized that the immune response elicited by radiotherapy may be as important as the radiation itself for successful treatment. More specifically, immunomodulatory cytokines may enhance the effectiveness of radiotherapy. To investigate this hypothesis, we measured changes in the serum interferon-gamma (IFN-γ) and interleukin-2 (IL-2) concentrations during radiotherapy and compared these modifications with outcomes. We found that serum concentrations of IL-2 and IFN-γ were positively associated with local response to radiotherapy in esophageal cancer. More generally, the intensity of the radiotherapy-elicited immune response was positively associated with local response to radiotherapy in esophageal cancer. Changes in serum IL-2 and IFN-γ concentrations were further associated with increased risks of acute hematologic toxicity and acute organ toxicity of the esophagus, lung, and skin. These results suggest that deciphering the mechanisms of radiotherapy-elicited immune response may help in the development of therapeutic interventions that would enhance the efficacy of radiotherapy and convert some ineffective responses to effective responses.

Apoptin sensitizes radiation-induced cell death via classic mitochondrial, caspase and p53-dependent signaling in HepG2 cells

Resistance or insensitivity to radiation therapy is one of the hallmarks of hepatocellular carcinoma. Sensitizing radioresistant cancer by combining radiation with other therapeutics to induce apoptosis has been widely investigated. Our previous study showed that chicken anaemia virus-derived apoptin protein induced the apoptosis of hepatic carcinoma HepG2 cells. In the present study, we demonstrated that apoptin sensitizes cells to radiation-induced apoptosis using a lentivirus-apoptin expression system in hepatic carcinoma HepG2 cells. Combination therapy with radiation and apoptin dramatically induced mitochondrial cytochrome c release and the cleavage of caspases -9, -3 and -7. Our findings are also the first to show that the combination of radiation and apoptin up-regulates p53 expression. Thus, apoptin treatment represents a potential method for enhancing the effectiveness of radiotherapy in poorly responding hepatocellular carcinoma.

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.