BOUNDEDNESS OF A CHEMOTAXIS-CONVECTION MODEL DESCRIBING TUMOR-INDUCED ANGIOGENESIS

This paper is concerned with the parabolic-parabolic-elliptic system■in a bounded domainΩ?Rnwith a smooth boundary,where the parametersχ,ζ1,ζ2are positive constants and m≥1.Based on the coupled energy estimates,the boundedness of the global classical solution is established in any dimensions(n≥1)provided that m>1.

Predictive value of tumor markers in patients with recurrent hepatocellular carcinoma in different vascular invasion pattern

BACKGROUND： Four tumor markers for hepatocellular carcinoma（HCC）, alpha-fetoprotein（AFP）, glypican-3（GPC3）, vascular endothelial growth factor（VEGF） and des-gammacarboxy prothrombin（DCP）, are closely associated with tumor invasion and patient＇s survival. This study estimated the predictability of preoperative tumor marker levels along with pathological parameters on HCC recurrence after hepatectomy.METHODS： A total of 140 patients with HCC who underwent hepatectomy between January 2012 and August 2012 were enrolled. The demographics, clinical and follow-up data were collected and analyzed. The patients were divided into two groups： patients with macroscopic vascular invasion（Ma VI ＋） and those without Ma VI（Ma VI-）. The predictive value of tumor markers and clinical parameters were evaluated by univariate and multivariate analysis.RESULTS： In all patients, tumor size（〉8 cm） and Ma VI were closely related to HCC recurrence after hepatectomy. For Ma VI＋ patients, VEGF（〉900 pg/m L） was a significant predictor for recurrence（RR=2.421; 95% CI： 1.272-4.606; P=0.007）. The 1- and 2-year tumor-free survival rates for Ma VI＋ patients with VEGF ≤900 pg/m L versus for those with VEGF 〉900 pg/m L were 51.5% and 17.6% versus 19.0% and 4.8%（P〈0.001）. For Ma VI- patients, DCP 〉445 m Au/m L and tumor size 〉8 cm were two independent risk factors for tumor recurrence（RR=2.307, 95% CI： 1.132-4.703, P=0.021; RR=3.150, 95% CI： 1.392-7.127, P=0.006; respectively）. The 1- and 2-year tumor-free survival rates for the patients with DCP ≤445 m Au/m L and those with DCP 〉445 m Au/m L were 90.4% and 70.7% versus 73.2% and 50.5% respectively（P=0.048）. The 1-and 2-year tumor-free survival rates for the patients with tumor size ≤8 cm and 〉8 cm were 83.2% and 62.1% versus 50.0% and 30.0%, respectively（P=0.003）.CONCLUSIONS： The Ma VI＋ patients with VEGF ≤900 pg/m L had a relatively high tumor-free survival than those with VEGF 〉900 pg/m L. In the Ma VI- patients, DCP 〉445 m Au/m L and tumor size 〉8 cm were predictive factors for postoperative recurrence.

ULTRASTRUCTURAL STUDY ON THE INVASION OF RETINAL INNER LIMITING MEMBRANE BY THE MALIGNANT TUMOR CELLS

To observe the process of invasion, retina of rat was used as a model to substitute the inner limiting membrane of retina for the basement membrane. Retina invaded by esophageal carcinoma cells and B16 melanoma cells upon the inner limiting membrane was studied by scanning and transmission electron microscopy. The results showed that the inner limiting membrane was destroyed by both kinds of tumor cells. The process of destruction was followed by a series of transformations in the inner limiting membrane, i.e. folding, swelling, thickening, and granular change. The inner limiting membrane was dissolved focally as a result of transformation, and then tumor cells invaded the retina through these dissolved regions. It seems that, as a barrier, the inner limiting membrane plays a similar role as the basement membrane.

Recurrence and metastasis of hepatocellular carcinoma: progress and prospects

Background: Recurrence after resection of hepatocellu-lar carcinoma(HCC) is a major obstacle to improveprognosis. Therefore, further improvement of long-term survival may depend on prevention and treat-ment of the recurrent tumor.Objective: To evaluate the progress of surgery forHCC, the risk factors for recurrence, and clinical andbasic studies on the prevention and management of re-currence and metastasis after resection of HCC.Data sources: A review of currently available data inthe mentioned areas.Data synthesis: Encouraging changes in the prognosticpattern were observed when the primary liver cancer(PLC) data of 1958-1967 (n=118), 1968-1977 (n=356), 1978-1987(n=715) and 1988-1997 (n=2038)were compared. The 5-year survival was 2.8%, 7.3%,27.1% and 52.5%, respectively, and the 10-yearsurvival 2.8%, 4.3%, 19.8% and 39.9%, respective-ly. Risk factors for recurrence included symptomaticpatient, high γ-glutamyl-peptidase (γ-PGT), largetumor size, portal vein embolus, advanced tumorstage, etc. Active hepatitis activity in the nontumorousliver and perioperative transfusion enhanced the re-currence. Molecular research into the invasiveness ofHCC identified some factors positively related to inva-siveness: p16 and p53 mutation, H-ras, c-cerbB2,mdm2, transforming growth factor (TGF), epidermalgrowth factor receptor (EGF-R), matrix metallopro-teinase-2 (MMP-2), urokinasetype plasminogen acti-vator (uPA), its receptor (uPA-R) and inhibitor(PAI-1), intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF),platelet-derived endothelial cell growth factor (PD-ECGF), and basic fibroblast growth factor (bFGF).In contrast, some factors were negatively related toHCC invasiveness: nm23-H1, Kai-1, tissue inhibitor ofmetalloproteinase-2 (TIMP-2), integrin 5, and E-cadherin. Re-resection of subclinical recurrence yield-ed a 5-year survival of 56.0% calculated from the firstresection (n=202) .Postoperative transarterialchemoembolization (TACE, n=103), hepatic arterycannulation during operation (n=105), postoperativebiotherapy (n=49), and cryohepatectomy (cryosurgeryfollowed by immediate resection of the frozen tumor,n=84) might decrease the recurrence rate, and the3-year recurrence rate was 7.6%, 18.0%, 11.1%, and30.1%, respectively. Minimal intraoperative blood lossand transfusion could reduce postoperative recurrence,although the exact mechanism remains to be elucidat-ed.Conlusions: HCC invasiveness is the major topic to bestudied, particularly in the molecular level. Anti-an-giogenesis, biotherapy, novel approach based on molec-ular findings, and multidisciplinary interventions mightalso be important for HCC.

Decreased invasion ability of hypotaurine synthesis deficient glioma cells was partially due to hypomethylation of Wnt5a promoter

Glioma is one of the lethal central nervous system tumors.The infiltrative and invasive growth nature makes it difficult to identify the boundary between glioma and the normal tissues,resulting in inevitable recurrence after surgery operation.Gliomas do not metastasize,so to prevent the residual tumor from proliferating or invading is a key challenge.Previous report indicated that hypotaurine could facilitate glioma invasion and suppress demethylases’activities.Using a hypotaurine synthesis deficient U251 cell line,we proved that the cells invasion ability was impaired.Gene expression profile analysis exhibited that knocking down one of the key enzymes of hypotaurine synthesis,2-aminoethanethiol dioxygenase(ADO),significantly affected the extracellular matrix-receptor process.Of that process,Wnt5a expression was severely upregulated by decreased intracellular ADO expression.Cells cultured at the presence of hypotaurine showed a decrease in intracellular Wnt5a protein and mRNA levels.This phenotype was due to hypermethylation of Wnt5a promoter,which was most likely the result of hypotaurine’s inhibiting demethylases activities.Collectively,this study demonstrated that hypotaurine synthesis deficient U251 cells were prone to epigenetic modification and Wnt5a seemed to be a tumor suppressor under that circumstance.This tumor suppression effect is warranted to be reevaluated in real tumor samples and the relevant evidence might contribute to develop new glioma interference strategies.

How useful is rectal endosonography in the staging of rectal cancer?

It is essential in treating rectal cancer to have adequate preoperative imaging,as accurate staging can influence the management strategy,type of resection,and candidacy for neoadjuvant therapy.In the last twenty years,endorectal ultrasound(ERUS) has become the primary method for locoregional staging of rectal cancer.ERUS is the most accurate modality for assessing local depth of invasion of rectal carcinoma into the rectal wall layers(T stage) .Lower accuracy for T2 tumors is commonly reported,which could lead to sonographic overstaging of T3 tumors following preoperative therapy.Unfortunately,ERUS is not as good for predicting nodal metastases as it is for tumor depth,which could be related to the unclear definition of nodal metastases.The use of multiple criteria might improve accuracy.Failure to evaluate nodal status could lead to inadequate surgical resection.ERUS can accurately distinguish early cancers from advanced ones,with a high detection rate of residual carcinoma in the rectal wall.ERUS is also useful for detection of local recurrence at the anastomosis site,which might require fine-needle aspiration of the tissue.Overstaging is more frequent than understaging,mostly due to inflammatory changes.Limitations of ERUS are operator and experiencedependency,limited tolerance of patients,and limited range of depth of the transducer.The ERUS technique requires a learning curve for orientation and identification of images and planes.With sufficient time and effort,quality and accuracy of the ERUS procedure could be improved.

Predictive factors for lymph node metastasis in early gastric cancer

AIM: To analyze the predictive factors for lymph node metastasis (LNM) in early gastric cancer (EGC). METHODS: Data from patients surgically treated for gastric cancers between January 1994 and December 2007 were retrospectively collected. Clinicopathological factors were analyzed to identify predictive factors for LNM. RESULTS: Of the 2936 patients who underwent gas-trectomy and lymph node dissection, 556 were diag-nosed with EGC and included in this study. Among these, 4.1% of patients had mucosal tumors (T1a) with LNM while 24.3% of patients had submucosal tumorswith LNM. Univariate analysis found that female gen-der, tumors ≥ 2 cm, tumor invasion to the submucosa, vascular and lymphatic involvement were significantly associated with a higher rate of LNM. On multivariate analysis, tumor size, lymphatic involvement, and tumor with submucosal invasion were associated with LNM. CONCLUSION: Tumor with submucosal invasion, size ≥ 2 cm, and presence of lymphatic involvement are predictive factors for LNM in EGC.

The ratio of MMP-2 to TIMP-2 in hilar cholangiocarcinoma:a semi-quantitative study

BACKGROUND: Hilar cholangiocarcinoma is associated with low resectability and poor survival. The aim of this study was to evaluate the roles of matrix metalloproteinases- 2 (MMP-2 ) and its tissue inhibitor of metalloproteinase-2 (TIMP-2) in tumor invasion or as a prognostic factor in patients with human hilar cholangiocarcinoma. METHODS: The expressions of MMP-2 and TIMP-2 were investigated in patients. Paraffinized tissue sections ob- tained from 50 patients with human hilar cholangiocarcino- ma were analysed. The expressions of MMP-2 and TIMP-2 were examined immunohistochemically. Image analysis with image-pro plus analysis software was used to semi- quantitatively determine the ratio of MMP-2 to TIMP-2. RESULTS: The expression levels of MMP-2 and TIMP-2 were strongly associated with tumor hepatic invasion in pa- tients with hilar cholangiocarcinoma. Significant diffe- rences in the ratio of MMP-2 to TIMP-2 between some pathologic factors were observed in patients with hilar cholangiocarcinoma. CONCLUSIONS: MMP-2 plays an essential role in tumor invasion and metastasis,while TIMP-2 is shown to strongly inhibit cancer invasion and metastasis. The ratio of MMP-2 to TIMP-2 may be a prognostic indicator for patients with hilar cholangiocarcinoma.

In Vitro Invasive Pattern of Hepatocellular Carcinoma Cell Line HCCLM9 Based on Three-dimensional Cell Culture and Quantum Dots Molecular Imaging

Summary： This study aimed to establish a new in vitro three-dimensional （3D） cell culture and use quantum dots （QDs） molecular imaging to examine the invasive behaviors of hepatocellular carcinoma （HCC） cells. Each well of the 24-well cell culture plate was cover-slipped. Matrigel diluted with se- rum-free DMEM was added and HCCLM9 cells were cultured on the Matrigel. The cell morphological and cell growth characteristics were observed by inverted microscopy and laser confocal microscopy at different culture time. Cell invasive features were monitored by QDs-based real-time molecular imaging techniques. The results showed that on this 3D cell culture platform, HCCLM9 cells exhibited typical multi-step invasive behaviors, including reversion of cell senescence, active focal proliferation and dominant clones invasion. During the process, cells under 3D cell culture showed biological behaviors of spatio-temporal characteristics. Cells first merged on the surface of matrix, then gradually infiltrated and migrated into deep part of matrix, presenting polygonal morphology with stretched protrusions, forming tubular, annular and even network structure, which suggested that HCC cells have the morpho- logical basis for vasculogenic mimicry. In addition, small cell clones with their edges well-circumscribed in early stage, progressed into a large irregular clone with ill-defined edge, while the other cells developed invadopodia. And QDs probing showed MT1-MMP was strongly expressed in the invadopodia. These findings indicate that a novel 3D cell culture platform has been successfully estab- lished, which can mimic the in vivo tumor microenvironment, and when combined with QDs-based mo- lecular imaging, it can help to better investigate the invasive behaviors of HCC cells.

Construction of Antisense RNA Expression Plasmid for u-PAR and Its Transfection to Highly Invasive PC-3M Cell Subclones

To evaluate the specific inhibition of antisense u PAR on the u PAR expressions in highly invasive cell subclones and to determine its blocking function in the invasion by those cells, a cDNA fragment of u PAR obtained by RT PCR was inserted into a plasmid vector named pcDNA3 in antisense orientation. Then the antisense u PAR recombinant was transfected into highly invasive cell subclones. The u PAR expression in neo resistant cells was examined by RT PCR and immunohistochemical assay. Compared to the control cells, the content of mRNA and protein of u PAR in transfected cells decreased sharply, and the rate of inhibition was 53 % and 73 %, respectively, indicating that an antisense u PAR might have played a specific inhibitory role in its expression in the cells, which may provide a good cell model for making further investigation of the inhibitory effects of the antisense u PAR on invasion in highly invasive cell subclones of human prostate carcinoma.

Histopathological Features of Invasion of Breast Invasive Ductal Carcinoma and Safety of Breast-conserving Surgery

In order to investigate the relationship between the extent of tumor invasion and the tumor size, axillary lymph nodes metastasis, Her-2 gene overexpression, and histologic grading in breast invasive ductal carcinoma as well as the optimal extent of excision during the breast-serving surgery, the clinical data of 104 patients with breast invasive ductal carcinoma who had received modified radical mastectomy were analyzed. The correlation analysis on invasive extent, which was evaluated by serial sections at an interval of 0.5 cm from 4 different directions taking the focus as the centre, and the tumor size, axillary lymph nodes metastasis, Her-2 gene overexpression, and his- tologic grading was processed. There was a significant correlation between invasive extent and tumor size （r=-0.766, P〈0.01）, and lymph nodes metastases 0=0.574, P〈0.01）, but there was no significant correlation between invasive extent and Her-2 expression （r=-0.106, P〉0.05）, and histologic grading （r=-0.228, P〉0.05）. The 100% negative rate of infiltration in patients without nipple discharge with tumor size 〈2, 2-3 and 〉3 cm was obtained at 1.5, 2.0 and 2.5 cm away from the tumor respectively. It is concluded that the performance of breast-serving surgery in patients with breast invasive ductal carcinoma should be evaluated by tumor size in combination with axillary lymph nodes involvement to decide the possibility of breast-serving and the secure excision extent.

The Inhibitory Effects of an Antisense u-PAR Vector on Invasion of Highly Invasive Human Prostate Carcinoma PC-3M Cell Subclones

To observe the inhibitory effects of an antisense u-PAR vector on invasion of highly invasive PC-3M cell subclones, the effects of the antisense u-PAR on activity of MMP-9 in those highly invasive cell subclones were detected by a quantitative RT-PCR and zymography. The monolayer invasion assay and colony formation assay in soft agar were used. And tumorigenesis rate and invasions by the cell subclones with or without the antisense u-PAR were observed in nude mice. It was found that in vitro growth of highly invasive PC-3M cell subclones transfected with the antisense u-PAR was declined, and the ability of anchorage-independent growth of those cell subclones was found decreased sharply, with the inhibiting rate becoming 79%and 60% , respectively. Although the anti-sense u-PAR didn't change MMP-9 gene transcription, they could inhibit the activation of MMP-9 of highly invasive PC-3M cell subclones. Moreover, the tumorigenesis rate of the cell subclones with the antisense u-PAR decreased and the growth of a neoplasm also slowed down. The t tests showed the difference between experimental and control groups was statistically significant (P<0.01). The anti-sense u-PAR vector could not only inhibit the invasion ability of highly invasive PC-3M cell subclones in vitro but also restrain the growth of those cell subclones in vivo.

Reductive lipid nanoparticles loaded with vinorelbine inhibit chemotherapy-induced invasion of cancer cells by modulating ENPP2

Cancer is a predominant culprit behind worldwide death and accounts for up to 10 million deaths every year.Chemotherapy is the primary therapeutic method employed for cancer in clinical settings and is essential in controlling tumor progression.Despite the advances in this field,tumor invasion and metastasis during treatment remain a significant cause of treatment failure.Nevertheless,the underlying mechanisms involving such a disappointing phenomenon are still not fully elucidated.Vinorelbine(VNB)extends the lifespan of many cancer patients in the clinic as an emerging chemotherapy drug approved by Food and Drug Administration(FDA).However,VNB-induced tumor metastasis is still an intractable problem,which may be closely related to the abnormal oxidative stress generated during VNB-mediated treatment.Hence,the study aims to construct a reductive nanosystem loaded with VNB,called VNB-VNP,to improve cancer cure rates and reduce tumor metastasis.With the reductive component vitamin E,VNB-VNP can effectively reduce oxidative stress and significantly outperform free VNB in preventing tumor progression.The transcriptome analysis shows that VNB-VNP can alleviate the over-expression of ectonucleotide pyrophosphatase/phosphodiesterase 2(ENPP2),which may be the main reason why VNB-VNP can inhibit tumor invasion and metastasis.Overall,the research designs a new platform for VNB treatment,which demonstrates promising efficacy in inhibiting neoplastic progression and identifies a new mechanism associated with VNB-induced tumor metastasis,which may offer several valuable references for enhancing chemotherapy efficacy in clinical anti-tumor therapy.

Research progress on FASN and MGLL in the regulation of abnormal lipid metabolism and the relationship between tumor invasion and metastasis

Tumorigenesis involves metabolic reprogramming and abnormal lipid metabolism,which is manifested by increased endogenous fat mobilization,hypertriglyceridemia,and increased fatty acid synthesis.Fatty acid synthase(FASN)is a key enzyme for the de novo synthesis of fatty acids,and monoacylglycerol esterase(MGLL)is an important metabolic enzyme that converts triglycerides into free fatty acids.Both enzymes play an important role in lipid metabolism and are associated with tumor-related signaling pathways,the most common of which is the PI3K–AKT signaling pathway.They can also regulate the immune microenvironment,participate in epithelial–mesenchymal transition,and then regulate tumor invasion and metastasis.Current literature have shown that these two genes are abnormally expressed in many types of tumors and are highly correlated with tumor migration and invasion.This article introduces the structures and functions of FASN and MGLL,their relationship with abnormal lipid metabolism,and the mechanism of the regulation of tumor invasion and metastasis and reviews the research progress of the relationship of FASN and MGLL with tumor invasion and metastasis.

Surgical treatment of hepatocellular carcinoma and related basic research with special reference to recurrence and metastasis

To summarize the progress of surgical treatment of hepatocellular carcinoma (HCC) and related basic research at the Liver Cancer Institute of Shanghai Medical University in the recent years, with special reference to recurrence and metastasis Methods Published and unpublished update clinical and experimental data in the above mentioned areas are summarized Results Surgical resection has played an important role in improving prognosis of HCC, the 5 year survival were 63 4% for small HCC resection (n=806), 39 6% for large HCC resection (n=1061), 64 7% for cytoreduction (using hepatic artery cannulation and ligation) and sequential resection of initially unresectable HCC (n=93), 56 0% for cytoreduction using transcatheter arterial chemoembolization (TACE) and followed by resection (n=65), and 22 4% for hepatic resection with removal of tumor thrombi in portal vein (n=103) Unfortunately, the 5 year recurrent rate after curative resection of HCC was up to 61 5%, which was mainly a result of intrahepatic “metastasis” and multicentric origin of HCC Clinically, re resection of subclinical recurrence yielded 56% of 5 year survival (n=202); prevention of recurrence by transcatheter arterial chemoembolization (TACE)+Interferon, or LAK/IL 2 therapy have decreased 3 year recurrent rate from 33% to 11%-18% In experimental aspect, metastatic human HCC model in nude mice (LCI D20) and HCC cell line with metastatic potential (MHCC97) have been established; studies on HCC invasiveness in the molecular level revealed similar results that reported in other solid cancers, and small HCC showed slightly better biological characteristics as compared with large HCC; microvessel density (MVD) that reflecting angiogenesis adversely correlated with 5 year survival of small HCC; experimental interventions using antisense H ras, bispecific antibody, BB94, as well as anti angiogenic agents (TNP470, suramin, CAI, heparin, antisense VEGF, etc ) have been demonstrated to inhibit tumor growth and lung metastasis in nude mice model Conclusions Recurrence and metastasis are the major obstacle to further improve prognosis of HCC, studies should be conducted both in clinical and experimental aspects, “HCC invasiveness” will be the major target to be studied, particularly in the molecular level, and anti angiogenesis will be one of the important approach

A nomogram predicting the recurrence of hepatocellular carcinoma in patients after laparoscopic hepatectomy

Background:Patients with hepatocellular carcinoma(HCC)undergoing surgical resection still have a high 5-year recurrence rate(~60%).With the development of laparoscopic hepatectomy(LH),few studies have compared the efficacy between LH and traditional surgical approach on HCC.The objective of this study was to establish a nomo-gram to evaluate the risk of recurrence in HCC patients who underwent LH.Methods:The clinical data of 432 patients,pathologically diagnosed with HCC,underwent LH as initial treatment and had surgical margin>1 cm were collected.The significance of their clinicopathological features to recurrence-free survival(RFS)was assessed,based on which a nomogram was constructed using a training cohort(n=324)and was internally validated using a temporal validation cohort(n=108).Results:Hepatitis B surface antigen(hazard ratio[HR],1.838;P=0.044),tumor number(HR,1.774;P=0.003),tumor thrombus(HR,2.356;P=0.003),cancer cell differentiation(HR,0.745;P=0.080),and microvascular tumor invasion(HR,1.673;P=0.007)were found to be independent risk factors for RFS in the training cohort,and were used for con-structing the nomogram.The C-index for RFS prediction in the training cohort using the nomogram was 0.786,which was higher than that of the 8th edition of the American Joint Committee on Cancer TNM classification(C-index,0.698)and the Barcelona Clinic Liver Cancer staging system(C-index,0.632).A high consistency between the nomogram prediction and actual observation was also demonstrated by a calibration curve.An improved predictive benefit in RFS and higher threshold probability of the nomogram were determined by receiver operating characteristic curve analysis,which was also confirmed in the validation cohort compared to other systems.Conclusions:We constructed and validated a nomogram able to quantify the risk of recurrence after initial LH for HCC patients,which can be clinically implemented in assisting the planification of individual postoperative surveil-lance protocols.