Central Region Of Tumor Research Articles

Image-based Classification of Tumor Type and Growth Rate using Machine Learning: a preclinical study

Medical images such as magnetic resonance (MR) imaging provide valuable information for cancer detection, diagnosis, and prognosis. In addition to the anatomical information these images provide, machine learning can identify texture features from these images to further personalize treatment. This study aims to evaluate the use of texture features derived from T1-weighted post contrast scans to classify different types of brain tumors and predict tumor growth rate in a preclinical mouse model. To optimize prediction models this study uses varying gray-level co-occurrence matrix (GLCM) sizes, tumor region selection and different machine learning models. Using a random forest classification model with a GLCM of size 512 resulted in 92%, 91%, and 92% specificity, and 89%, 85%, and 73% sensitivity for GL261 (mouse glioma), U87 (human glioma) and Daoy (human medulloblastoma), respectively. A tenfold cross-validation of the classifier resulted in 84% accuracy when using the entire tumor volume for feature extraction and 74% accuracy for the central tumor region. A two-layer feedforward neural network using the same features is able to predict tumor growth with 16% mean squared error. Broadly applicable, these predictive models can use standard medical images to classify tumor type and predict tumor growth, with model performance, varying as a function of GLCM size, tumor region, and tumor type.

Intratumor Heterogeneity in Interstitial Fluid Pressure in Cervical and Pancreatic Carcinoma Xenografts

Preclinical studies have suggested that interstitial fluid pressure (IFP) is uniformly elevated in the central region of tumors, whereas clinical studies have revealed that IFP may vary among different measurement sites in the tumor center. IFP measurements are technically difficult, and it has been claimed that the intratumor heterogeneity in IFP reported for human tumors is due to technical problems. The main purpose of this study was to determine conclusively whether IFP may be heterogeneously elevated in the central tumor region, and if so, to reveal possible mechanisms and possible consequences. Tumors of two xenograft models were included in the study: HL-16 cervical carcinoma and Panc-1 pancreatic carcinoma. IFP was measured with Millar SPC 320 catheters in two positions in each tumor and related to tumor histology or the metastatic status of the host mouse. Some tumors of both models showed significant intratumor heterogeneity in IFP, and this heterogeneity was associated with a compartmentalized histological appearance (i.e., the tissue was divided into compartments separated by thick connective tissue bands) in HL-16 tumors and with a dense collagen-I-rich extracellular matrix in Panc-1 tumors, suggesting that these connective tissue structures prevented efficient interstitial convection. Furthermore, some tumors of both models developed lymph node metastases, and of the two IFP values measured in each tumor, only the higher value was significantly higher in metastatic than in non-metastatic tumors, suggesting that metastatic propensity was determined by the tumor region having the highest IFP.

RETRACTED: Tumor-secreted GRP78 facilitates the migration of macrophages into tumors by promoting cytoskeleton remodeling

Glucose-regulated protein 78 (GRP78), an important molecular chaperone in the endoplasmic reticulum, is often over-expressed in the central region of advanced tumor and acts as a promoter of tumor progression. As main immune cells in the tumor microenvironment, infiltration of abundant macrophages into advanced tumor further facilitates growth of tumor. Although has potential association between GRP78 and infiltration of macrophages, its underlying mechanisms are poorly understood. Here, we report that secreted GRP78 facilitates recruitment of macrophages into tumors both in vitro and in vivo. Further studies reveal that secreted GRP78 transports into macrophages and bound to intracellular Ca2+, which lead to uneven distribution of Ca2+ and subsequent polarization of macrophages. The polarization of macrophages activates expression of microRNA-200b-3p. By directly targeting RhoGDI, miR-200b-3p stimulates the activity of RhoGTPase and ultimately leads to the distribution of GTP-Rac1 and GTP-Cdc42 in front protrusion and GTP-RhoA in rear contraction, which further results in migration of macrophages in a certain direction. Our results reveal a novel function of GRP78 to promote the recruitment of macrophages to tumor and provide a potential therapeutic target for malignancies.

Na+,HCO3- cotransporter NBCn1 accelerates breast carcinogenesis.

Cell metabolism increases during carcinogenesis. Yet, intracellular pH in solid cancer tissue is typically maintained equal to or above that of normal tissue. This is achieved through accelerated cellular acid extrusion that compensates for the enhanced metabolic acid production. Upregulated Na+,HCO3- cotransport is the predominant mechanism of net acid extrusion in human and murine breast cancer tissue, and in congruence, the protein expression of the electroneutral Na+,HCO3- cotransporter NBCn1 is increased in primary breast carcinomas and lymph node metastases compared to matched normal breast tissue. The capacity for net acid extrusion and level of steady-state intracellular pH are lower in carcinogen- and ErbB2-induced breast cancer tissue from NBCn1 knockout mice compared to wild-type mice. Consistent with importance of intracellular pH control for breast cancer development, tumor-free survival is prolonged and tumor growth rate decelerated in NBCn1 knockout mice compared to wild-type mice. Glycolytic activity increases as function of tumor size and in areas of poor oxygenation. Because cell proliferation in NBCn1 knockout mice is particularly reduced in larger-sized breast carcinomas and central tumor regions with expected hypoxia, current evidence supports that NBCn1 facilitates cancer progression by eliminating intracellular acidic waste products derived from cancer cell metabolism. The present review explores the mechanisms and consequences of acid-base regulation in breast cancer tissue. Emphasis is on the Na+,HCO3- cotransporter NBCn1 that accelerates net acid extrusion from breast cancer tissue and thereby maintains intracellular pH in a range permissive for cell proliferation and development of breast cancer.

Nano-drug System Based on Hierarchical Drug Release for Deep Localized/Systematic Cascade Tumor Therapy Stimulating Antitumor Immune Responses.

Inaccessibility of deep-seated malignant cells in the central region of tumors and uncontrollable tumor recurrence represent a significant challenge for conventional synergistic cancer therapy. Herein, we designed a novel nanoplatform based on hierarchical drug release for deep cascade cancer therapy including localized photothermal therapy, systematic chemotherapy, and elicited immune responses.Methods: The first-step chemotherapy could be carried out by polydopamine (PDA) releasing doxorubicin (DOX) in the specific microenvironment of lysosomes (pH 5.5). The branched gold nanoshells and PDA converted the light to heat efficiently to accomplish the second-step photothermal therapy and collapsed biomimetic vesicles (BVs) to release paclitaxel (PTX), which promoted the third-step of chemotherapy and triggered immune responses.Results: After 10 days of treatment, there were no obvious residual tumors in tumor-bearing mice. Significantly, 10 days after stopping treatment, mice in the drug immune-therapeutic group showed little tumor recurrence (1.5 times) compared to substantial recurrence (20 times) in the conventional treatment group.Conclusion: The hierarchical drug release and cascade therapeutic modality enhance the penetration of drugs deep into the tumor tissue and effectively inhibit recurrence. This cascade therapeutic modality provides a novel approach for more effective cancer therapy.

Extracellular Matrix Imaging of Breast Tissue Pathologies by MALDI-Imaging Mass Spectrometry.

A new method accessing proteins from extracellular matrix by imaging mass spectrometry (ECM IMS) has been recently reported. ECM IMS is evaluated for use in exploring breast tissue pathologies. A tissue microarray (TMA) is analyzed that has 176 cores of biopsies and lumpectomies spanning breast pathologies of inflammation, hyperplasia, fibroadenoma, invasive ductal carcinoma, and invasive lobular carcinoma and normal adjacent to tumor (NAT). NAT is compared to subtypes by area under the receiver operating curve (ROC) >0.7. A lumpectomy is also characterized for collagen organization by microscopy and stromal protein distribution by IMS. LC-based high-resolution accurate mass (HRAM) proteomics is used to identify proteins from the lumpectomy. TMA analysis shows distinct spectral signatures reflecting a heterogeneous tissue microenvironment. Ninety-four peaks show an ROC >0.7 compared to NAT; NAT has overall higher intensities. Lumpectomy analysis by IMS visualizes a complex central tumor region with distal tumor regions. A total of 39 stromal proteins are identified by HRAM LC-based proteomics. Accurate mass matches between image data and LC-based proteomics demonstrate a heterogeneous collagen type environment in the central tumor. Data portray the heterogeneous stromal microenvironment of breast pathologies, including alteration of multiple collagen-type patterns. ECM IMS is a promising new tool for investigating the stromal microenvironment of breast tissue including cancer.

Tumor-Secreted GRP78 Facilitates the Migration of Macrophages into Tumors by Promoting Cytoskeleton Remodeling

Glucose-regulated protein 78 (GRP78), an important molecular chaperone in the endoplasmic reticulum, is often over-expressed in the central region of advanced tumor and acts as a promoter of tumor progression. As main immune cells in the tumor microenvironment, infiltration of abundant macrophages into advanced tumor further facilitates growth of tumor. Although the potential association between GRP78 and infiltration of macrophages, its underlying mechanisms are poorly understood. Here, we reported that the level of secreted GRP78 was positively correlated with the malignant degree of tumor; and enhanced secretion of GRP78 facilitated recruitment of macrophages into tumors both in vitro and in vivo. Further studies revealed that secreted GRP78 was able to transport into macrophages and bound to intracellular Ca2 , which led to uneven distribution of Ca2 and subsequent polarization of macrophages. Furthermore, macrophages polarization promoted pro-adhesion by activating Fibronectin−integrin-β1−FAK pathway and accelerated MMP2/9 mediated extracellular matrix degradation that contributed to migration of macrophages. Polarization of macrophages also led to the distribution of GTP-Rac1 and GTP-Cdc42 in front protrusion and GTP-RhoA in rear contraction by activating RhoGTPase family members, which further resulted in migration of macrophages in a certain direction. Mechanistically, GRP78-mediated polarization of macrophages activated expression of microRNA-200b-3p. By directly targeting RhoGDI, miR-200b-3p stimulated the activity of RhoGTPase that facilitated cytoskeleton remodeling and subsequently polarization of macrophages. Together, our results reveal a novel function of GRP78 to promote the recruitment of macrophages to tumor and provide a potential therapeutic target for malignancies. Funding Statement: This work was supported by the National Natural Science Foundation of China (No. 31770382 and No. 81803791), “1331 project” Collaborative Innovation Center and team (1331 CIC). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All animal experiments conducted in this study were approved by the Institutional Animal Care and Use Committee of Shanxi University (Taiyuan, China). All of the experimental procedures were performed in accordance with the protocols and ethical regulations approved by the Institutional Animal Care and Use Committee of Shanxi University (Taiyuan, China).

Application of diffusion tensor imaging in infiltration zone investigation of high-grade gliomas

Objective To explore the invasion characteristics of high-grade gliomas and to quantitatively investigate their infiltration zone using diffusion tensor imaging (DTI). Methods Ten patients of frontal high-grade gliomas (WHO Ⅲ-Ⅳ) were retrospectively reviewed who were admitted to Neurosurgery Department of Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases from October 2014 to October 2016. All patients underwent the examination of preoperative MRI and DTI. Three regions of interest (ROI), which were placed at the enhanced central region of the tumor, 1cm and 2cm from the tumor edge, were determined on T1-weighted imaging with contrast medium. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of those ROIs were measured prior to surgery. Before the incision of dura matter, specimens of those ROIs were obtained under the guidance of navigation. Postoperative examinations of specimens including histological, tumor cell density, MMP-9 and Ki-67 were carried out. Differences in tumor cell density, MMP-9 and Ki-67 values among 3 ROIs were analyzed. Correlations among the ADC, FA values and the tumor cell density were also evaluated. Results As the distance from the tumor entity increased, tumor cell density, expression levels of MMP-9 and Ki-67 significantly decreased compared with those in tumor entity (all P<0.05). To analyze the relationship of tumor cell density to ADC and FA values, the canonical discriminant formula was as follows: D=0.201 ADC+ 1.094 FA, which could be used to determine the tumor cell density with an accuracy rate of 66.7%. Conclusions As the distance from tumor entity increased, tumor cell density, invasion and proliferation decrease significantly compared with the tumor entity. There seems to be a quantitative relationship between DTI parameters and tumor cell density of high-grade gliomas, which could contribute to the formulation of surgical plan. Key words: Glioma; Neoplasm invasiveness; Diffusion tensor imaging

Hepatocellular carcinoma-targeting oncolytic adenovirus overcomes hypoxic tumor microenvironment and effectively disperses through both central and peripheral tumor regions

Cancer-specific promoter driven replication of oncolytic adenovirus (Ad) is cancer-specific, but shows low transcriptional activity. Thus, we generated several chimeric α-fetoprotein (AFP) promoter variants, containing reconstituted enhancer and silencer regions, to preferentially drive Ad replication in hepatocellular carcinoma (HCC). Modified AFP promoter, containing 2 enhancer A regions and a single enhancer B region (a2bm), showed strong and HCC-specific transcription. In AFP-positive HCCs, gene expression was 43- to 456-fold higher than those of control AFP promoter lacking enhancers. a2bm promoter was further modified by inserting multiple hypoxia-responsive elements (HRE) to generate Ha2bm promoter, which showed stronger transcriptional activity than a2bm promoter under hypoxic conditions. Ha2bm promoter-regulated oncolytic Ad (Ha2bm-d19) showed a stronger antitumor and proapoptotic effect than did a2bm promoter-regulated oncolytic Ad (a2bm-d19) in HCC xenograft tumors. Systemically administered Ha2bm-d19 caused no observable hepatotoxicity, whereas control replication-competent Ad, lacking cancer specificity (d19), induced significant hepatic damage. Ha2bm-d19 caused significantly lower expression of interleukin-6 than d19, showing that HCC-targeted delivery of Ad attenuates induction of the innate immune response against Ad. This chimeric AFP promoter enabled Ad to overcome the hypoxic tumor microenvironment and target HCC with high specificity, rendering it a promising candidate for the treatment of aggressive HCCs.

Near-Infrared Upconversion Mesoporous Cerium Oxide Hollow Biophotocatalyst for Concurrent pH-/H2 O2 -Responsive O2 -Evolving Synergetic Cancer Therapy.

Tumor hypoxia is typically presented in the central region of solid tumors, which is mainly caused by an inadequate blood flow and oxygen supply. In the conventional treatment of hypoxic human tumors, not only the oxygen-dependent photodynamic therapy (PDT), but also antitumor drug-based chemotherapy, is considerably limited. The use of direct oxygen delivering approach with oxygen-dependent PDT or chemotherapy may potentiate the reactive oxygen species (ROS)-mediated cytotoxicity of the drug toward normal tissues. Herein, a synergetic one-for-all mesoporous cerium oxide upconversion biophotocatalyst is developed to achieve intratumorally endogenous H2 O2 -responsive self-sufficiency of O2 and near-infrared light controlled PDT simultaneously for overcoming hypoxia cancer. Furthermore, the sufficient O2 plays an important role in overcoming the chemotherapeutic drug-resistant cancer caused by hypoxia, therefore inducing tumor cell apoptosis significantly.

1078 Cutting Along the Central Region of Tumor With Endoscopic Submucosal Dissection: A Novel and Safe Technique for Gastric Leiomyoma More than 4cm in the Sub-Cardia Region (With Videos)

1078 Cutting Along the Central Region of Tumor With Endoscopic Submucosal Dissection: A Novel and Safe Technique for Gastric Leiomyoma More than 4cm in the Sub-Cardia Region (With Videos)

Abstract OT1-01-07: A phase 2 study of eribulin followed by doxorubicin and cyclophosphamide as preoperative therapy for HER2-negative inflammatory breast cancer

Abstract Background: HER2 negative(neg) inflammatory breast cancer(IBC) exhibits relative resistance to chemotherapy evidenced by pCR(pathologic complete response rate) rates of 12-25% with preoperative taxane/anthracycline regimens. Eribulin(Eisai®) inhibits microtubular function via sequestration of tubulin into nonfunctional aggregates, thus being effective against taxane-resistant cancer. Preclinical data shows 2 mechanisms of action: reversion of EMT(epithelial to mesenchymal transition) and normalization of tumor vascularity. Treatment of triple negative breast cancer(TNBC) cell-lines with eribulin results in downregulation of mesenchymal markers with concomitant increase in expression of classical epithelial markers(Yoshida BJC 2014). In PDX models, eribulin improved blood perfusion in central region of tumors, increased vessel density, reduced vessel diameter, and reduced hypoxia. IBC is highly angiogenic, with increased microvessel density, higher fraction of proliferating endothelial cells and greater expression of pro-angiogenic genes compared with non-IBC(McCarthy CCR 2002). This preoperative study(EAC) exploits the angiogenic properties of IBC with the treatment scheme of eribulin(E) followed by doxorubicin/cyclosphosphamide(AC) in newly diagnosed HER2neg IBC. Methods: Pts with HER2neg Stage III (cT4d,any N,M0) IBC are eligible if they have not received prior therapy for BC, have adequate organ function, cardiac ejection fraction &amp;gt; 50%, and willing to undergo 2 research biopsies (rbx) of the affected breast. Following baseline rbx, pts receive cycle 1, day(d)1 eribulin 1.4 mg/m2. A 2nd rbx occurs on d8, prior to dosing of E. Following 3 more cycles of E(1.4mg/m2 d1,d8,every 21d), pts receive 4 cycles of dose-dense AC(A-60 mg/m2,C-600mg/m2 every 14d). Pts with adequate disease response undergo mastectomy/axillary lymph node dissection followed by chest wall/regional lymph node radiation. Adjuvant endocrine therapy is used if hormone receptor positive. An imaging sub-study evaluates tumor perfusion via DCE-MRI pre and post 1st dose E. Correlatives: To investigate whether E induces reversion of EMT in IBC, expression of 10 EMT-related genes are determined in each rbx, and normalization of tumor vessel phenotype are assessed by expression of 15 angiogenesis-related genes in rbx by RT-qPCR. Gene expression will be repeated on residual tumor at mastectomy. An imaging sub-study of DCE-MRI (10 pts) will assess vascular remodeling via changes in Ktrans , ve and vp determination of IBC region of interest, core and rim and changes in the iAUC computed pre and post 1st dose E. Statistics: The primary endpoint is pCR. A Simon two-stage design is used. If the proportion of pts having pCR is &amp;lt; 0.10 then EAC is considered minimally effective, versus alternative hypothesis that EAC is worthy of further study if proportion pCR &amp;gt; 0.30. In the 1st stage, if &amp;lt; 2/16 pts have pCR, the study is stopped; if &amp;gt; 3 pts have pCR, the study proceeds. In the 2nd stage, EAC is rejected if &amp;lt; 4 of 25 pts have a pCR(α=0.10;β=0.10). Up to 25 pts will be enrolled. Secondary endpoints are residual cancer burden, disease-free survival, time to treatment failure and overall survival. Clinical trial information: NCT02623972. Citation Format: Overmoyer B, Goel S, Regan M, Hirshfield-Bartek J, Schlosnagel E, Yeh E, Qin L, Bellon J, Nakhlis F, Jacene H, Winer E. A phase 2 study of eribulin followed by doxorubicin and cyclophosphamide as preoperative therapy for HER2-negative inflammatory breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-01-07.

Fractional Anisotropy Correlates with Overall Survival in Glioblastoma

Glioblastoma (GB) is an infiltrative disease that results in microstructural damage on a cellular level. Fractional anisotropy (FA) is an important estimate of diffusion tensor imaging (DTI) that can be used to assess microstructural integrity. The aim of this study was to examine the correlation between FA values and overall survival (OS) in patients with GB. This retrospective single-center study included 122 consecutive patients with GB (50 women; median age, 63 years) with preoperative MRI including fluid attenuated inversion recovery (FLAIR), contrast-enhanced T1-weighted sequences, and DTI. FA and apparent diffusion coefficient (ADC) values in contrast-enhancing lesions (FA-CEL, FA-ADC), nonenhancing lesions, and central tumor regions were correlated to histopathologic and clinical parameters. Univariate and multivariate survival analyses were performed. Patients with low FA-CEL (median <0.31) showed significantly improved OS in univariate analysis (P= 0.028). FA-CEL also showed a positive correlation with Ki-67 proliferation index (P= 0.003). However, in a multivariate survival model, FA values could not be identified as independent prognostic parameters beside established factors such as age and Karnofsky performance scale score. FA values in nonenhancing lesions and central tumor regions and mean ADC values had no distinct influence onOS. FA values can provide prognostic information regarding OS in patients with GB. There is a correlation between FA-CEL values and Ki-67 proliferation index, a marker for malignancy. Noninvasive identification of more aggressive GB growth patterns might be beneficial for preoperative risk evaluation and estimation of prognosis.

Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer.

A number of independent gene expression profiling studies have identified transcriptional subtypes in colorectal cancer with potential diagnostic utility, culminating in publication of a colorectal cancer Consensus Molecular Subtype classification. The worst prognostic subtype has been defined by genes associated with stem-like biology. Recently, it has been shown that the majority of genes associated with this poor prognostic group are stromal derived. We investigated the potential for tumor misclassification into multiple diagnostic subgroups based on tumoral region sampled. We performed multiregion tissue RNA extraction/transcriptomic analysis using colorectal-specific arrays on invasive front, central tumor, and lymph node regions selected from tissue samples from 25 colorectal cancer patients. We identified a consensus 30-gene list, which represents the intratumoral heterogeneity within a cohort of primary colorectal cancer tumors. Using a series of online datasets, we showed that this gene list displays prognostic potential HR = 2.914 (confidence interval 0.9286-9.162) in stage II/III colorectal cancer patients, but in addition, we demonstrated that these genes are stromal derived, challenging the assumption that poor prognosis tumors with stem-like biology have undergone a widespread epithelial-mesenchymal transition. Most importantly, we showed that patients can be simultaneously classified into multiple diagnostically relevant subgroups based purely on the tumoral region analyzed. Gene expression profiles derived from the nonmalignant stromal region can influence assignment of colorectal cancer transcriptional subtypes, questioning the current molecular classification dogma and highlighting the need to consider pathology sampling region and degree of stromal infiltration when employing transcription-based classifiers to underpin clinical decision making in colorectal cancer. Clin Cancer Res; 22(16); 4095-104. ©2016 AACRSee related commentary by Morris and Kopetz, p. 3989.

Expression and relationship between hepaCAM protein and multidrug resistance protein in renal carcinoma

Objective To investigate the expression and relationship between hepatocyte cell adhesion molecule (hepaCAM) protein and some multidrug resistance proteins in renal carcinoma tissue. Methods Expressions of hepaCAM, multidrug resistance associated protein (MRP), P-glycoprotein (P-gp), lung resistance protein (LRP), and topoisomerase Ⅱ (TOPO Ⅱ) protein were detected by immunohistochemistry in different areas of human renal cell carcinoma tissues and their relationships were analyzed. Results In the peripheral zone of renal tumor, hepaCAM, MRP, P-gp and LRP protein were showed positive expression. In the central region of the renal tumor, the expressions of hepaCAM, P-gp and LRP were negative or weakly positive, while the expressions of MRP and TOPO Ⅱ protein were positive. The expressions of MRP and TOPO Ⅱ protein in the central region of tumor were stronger than those in the peripheral zone of tumor (31.23±5.67 vs. 23.89±4.56; 45.66±2.34 vs. 5.23±0.66), with statistically significant differences (t=-6.20, P=0.00; t=-100.16, P=0.00). While the expressions of other proteins (hepaCAM, P-gp and LRP) in the central region of tumor were weaker than those in the peripheral zone of tumor (3.21±1.12 vs. 27.25±2.23; 2.34±0.33 vs. 51.23±3.45; 4.22±1.78 vs. 44.23±1.45), with statistically significant differences (t=60.87, P=0.00; t=90.35, P=0.00; t=107.18, P=0.00). Correlation analysis showed that the expression of hepaCAM protein in the central region of renal carcinoma was related with the expression of MRP protein (r=0.94, P=0.01), but it was not related with the expressions of P-gp, LRP and TOPO Ⅱ protein (r=0.22, P=0.44; r=0.14, P=0.80; r=0.34, P=0.07). Conclusion The expression of hepaCAM protein in renal carcinoma may be related to tumor drug-resistance. Key words: Kidney neoplasms; Cell adhesion molecules; Multidrug resistance-associated proteins

Combination of vascular disrupting agents and nanomedicines for solid tumor therapy

Event Abstract Back to Event Combination of vascular disrupting agents and nanomedicines for solid tumor therapy Xuesi Chen1*, Zhaohui Tang1* and Wantong Song1* 1 Changchun Institute of Applied Chemistry, CAS, Key Laboratory of Polymer Ecomaterials, China Introduction: Nanosized anticancer drug delivery systems hold great promise for safe, simple and effective therapies against malignant solid tumors. Due to the enhanced permeability and retention (EPR) effect of solid tumor tissues, nanoparticles can passively accumulate in tumors, and this resulted in more than ten nanocarrier-based drugs been marketed for the treatment of cancers. However, a main barrier for further improving the therapeutic efficiency of nanomedicines lies in the poor permeability of solid tumors. Especially in the tumor central regions, low penetration of nanoparticles results in low contact probability of drugs to reach a majority of tumor cells and limited therapeutic outcomes. Aiming at this problem, in this study, we proposed a novel strategy for enhancing the treatment efficacy of nanomedicines within the central regions of solid tumor by combining nanomedicines with vascular disrupting agents (VDAs). As shown in Figure 1, nanomedicines mainly act on the tumor periphery, while VDAs eradicate tumor cells in the central regions of a solid tumor. Therefore, the combination is expected to eradicate the entire tumor. Materials and Methods: A typical small-molecule VDA, combretastatin A4 disodium phosphate (CA4P), which is in phase I/II clinical trials was applied here. Cis-diamminedichloroplatinum loaded nanoparticles (CDDP-NPs) prepared from CDDP and poly(L-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG), which was previously reported and optimized by us was applied here as the model nanomedicine. For in vivo studies, Balb/C mice bearing murine colon carcinoma C26 tumors was applied. Results and Discussion: The effect of CA4P, CDDP-NPs and the combination on tumor necrosis after a single intravenous injection was compared by H-E staining. As shown in Figure 2, in contrast to CDDP-NPs or CA4P alone, the combination of CDDP-NPs+CA4P caused necrosis in both the central and peripheral regions, and resulted in a necrosis rate of 92.8±3.0%. In the following in vivo anticancer efficacy test, the combination group exhibited significant tumor growth suppression without significant bodyweight loss. Conclusion: Our work supports the notion that coadministration of nanomedicines plus vascular disrupting agents will serve as a promising strategy for the treatment of solid tumors with high efficacy and low side effects.

Improving Image Quality for Lung Cancer Imaging With Optimal Monochromatic Energy Level in Dual Energy Spectral Computed Tomography.

The aim of this study was to find optimal monochromatic spectral computed tomography (CT) level to improve image quality of lung cancer. Fifty patients with lung cancers were scanned by spectral CT; monochromatic images at 50, 60, 70 and 80 keV energy levels were generated; and objective analysis including image noise, lesion-to-lung contrast-to-noise ratio, and CT number difference between central and peripheral regions of tumor (dCT value) were measured and compared. Subjective assessment about the overall image quality and inhomogeneity enhancement was compared. The highest contrast-to-noise ratio value and subjective score of image quality were obtained at 70 keV, which were superior to those of 50- and 80-keV series (all P < 0.05). The subjective score of the inhomogeneity evaluation was peaked at 60-keV series and significantly higher than other energy levels (all P < 0.05). Both objective and subjective image analysis of lung cancers may be improved with the combined observation of 60 keV and 70 keV monochromatic images in spectral CT.

Resveratrol inhibits hypoxia-driven ROS-induced invasive and migratory ability of pancreatic cancer cells via suppression of the Hedgehog signaling pathway.

A hypoxic microenvironment is commonly found in the central region of solid tumors, including pancreatic cancer. Our previous study revealed that resveratrol plays an important role in suppressing the proliferation and EMT of pancreatic cancer cells. However, whether resveratrol could suppress hypoxia-induced cancer progression and the underlying mechanisms have not been fully elucidated. The aim of the present study was to evaluate whether resveratrol affects hypoxia-induced reactive oxygen species (ROS) production and the activation of the Hedgehog (Hh) signaling pathway as well as the invasion of pancreatic cancer. The human pancreatic cancer cell lines, BxPC-3 and Panc-1, were subjected to a hypoxic condition and three different concentrations of resveratrol. The intracellular ROS were determined using 2,7-dichlorodihydrofluorecein diacetate. Wound healing and Transwell invasion assays were used to detect the migratory and invasive potential of the cancer cells. Metastatic-related and Hh signaling-related factors were detected by qRT-PCR and western blot analysis. Immunofluorescence staining was used to test the nuclear translocation of GLI1. The results showed that the hypoxia-induced production of ROS was decreased by resveratrol in a concentration-dependent manner. Resveratrol significantly inhibited the hypoxia-stimulated invasion and migration of pancreatic cancer cells. Resveratrol inhibited hypoxia-induced HIF-1α protein expression. Resveratrol also suppressed hypoxia‑induced expression of metastatic-related factors, uPA and MMP2. In addition, resveratrol markedly inhibited hypoxia-mediated activation of the Hh signaling pathway. Furthermore, the antioxidant N-acetylcysteine (NAC) significantly suppressed the invasive and migratory ability of pancreatic cancer cells during hypoxia. Taken together, these data indicate that resveratrol plays an important role in suppressing hypoxia-driven ROS-induced pancreatic cancer progression by inhibiting the Hh signaling pathway, providing evidence that resveratrol may be a potential candidate for the chemoprevention of cancer.

Early effects of low dose bevacizumab treatment assessed by magnetic resonance imaging.

BackgroundAntiangiogenic treatments have been shown to increase blood perfusion and oxygenation in some experimental tumors, and to reduce blood perfusion and induce hypoxia in others. The purpose of this preclinical study was to investigate the potential of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and diffusion weighted MRI (DW-MRI) in assessing early effects of low dose bevacizumab treatment, and to investigate intratumor heterogeneity in this effect.MethodsA-07 and R-18 human melanoma xenografts, showing high and low expression of VEGF-A, respectively, were used as tumor models. Untreated and bevacizumab-treated tumors were subjected to DCE-MRI and DW-MRI before treatment, and twice during a 7-days treatment period. Tumor images of Ktrans (the volume transfer constant of Gd-DOTA) and ve (the fractional distribution volume of Gd-DOTA) were produced by pharmacokinetic analysis of the DCE-MRI data, and tumor images of ADC (the apparent diffusion coefficient) were produced from DW-MRI data.ResultsUntreated A-07 tumors showed higher Ktrans, ve, and ADC values than untreated R-18 tumors. Untreated tumors showed radial heterogeneity in Ktrans, i.e., Ktrans was low in central tumor regions and increased gradually towards the tumor periphery. After the treatment, bevacizumab-treated A-07 tumors showed lower Ktrans values than untreated A-07 tumors. Peripherial tumor regions showed substantial reductions in Ktrans, whereas little or no effect was seen in central regions. Consequently, the treatment altered the radial heterogeneity in Ktrans. In R-18 tumors, significant changes in Ktrans were not observed. Treatment induced changes in tumor size, ve, and ADC were not seen in any of the tumor lines.ConclusionsEarly effects of low dose bevacizumab treatment may be highly heterogeneous within tumors and can be detected with DCE-MRI.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1918-1) contains supplementary material, which is available to authorized users.

EPIG-15MicroRNA EXPRESSION HETEROGENEITY IN GLIOBLASTOMA

Intratumor heterogeneity exists in many cancers, with clear evidence of differential gene expression temporo-spatially in glioblastoma multiforme (GBM). MicroRNA (miRNA) profiling studies have identified risk-stratifying signatures in GBM, but it has not been clarified whether microRNA profiles vary in a similar fashion to gene expression within individual GBM tumors. This study utilized primary GBM specimens resected from patients undergoing surgery in a regional UK Neurosurgery unit. Fresh frozen tissue underwent RNA extraction and miScript Human Brain Cancer miRNA PCR Array was used to assess 84 miRNA's expression levels between distinct spatial regions within primary GBMs. miRNA expression was analyzed with quantitative RT-PCR and gene targets for analysis were selected with miRtarget gene prediction software. Protein levels for the in silico predicted targets based on miRNA expression were validated through immunohistochemistry (IHC). A large degree of intratumor heterogeneity was apparent in the samples. Homology existed between individuals with 8 common miRNAs differentially expressed between central and edge regions of tumors. Protein levels of CDK6 and c-KIT nuclear accumulation were significantly elevated at tumor edges relative to core samples in concordance with the microRNA profiling. Intratumor heterogeneity in GBM produces significant miRNA profiling variation depending on spatial location of the sample within the tumor. Therefore, assessment of GBM miRNA signatures requires selective sampling from multiple distinct tumor regions and consideration of the overall patterns of miRNA expression across the entirety of the tumor.