Different Regions Of Tumor Research Articles

Contrast-enhanced ultrasonography for early prediction of response of neoadjuvant chemotherapy in breast cancer.

Neoadjuvant chemotherapy (NAC) is widely accepted as a primary treatment for inoperable or locally advanced breast cancer before definitive surgery. However, not all advanced breast cancers are sensitive to NAC. Contrast-enhanced ultrasonography (CEUS) has been considered to assess tumor response to NAC as it can effectively reflect the condition of blood perfusion and lesion size. Therefore, this study aimed to evaluate the diagnostic performance of CEUS to predict early response in different regions of interest in breast tumors under NAC treatment. This prospective study included 82 patients with advanced breast cancer. Parameters of TIC (time-intensive curve) between baseline and after the first cycle of NAC were calculated for the rate of relative change (Δ), including Δpeak, ΔTTP (time to peak), ΔRBV (regional blood volume), ΔRBF (regional blood flow) and ΔMTT (mean transit time). The responders and non-responders were distinguished by the Miller-Payne Grading (MPG) system and parameters from different regions of tumors were compared in these two groups. For ROI 1(the greatest enhancement area in the central region of the tumor), there were significant differences in Δpeak1, ΔRBV1 and ΔRBF1 between responders and non-responders. For ROI 2 (the greatest enhancement area on edge of the tumor), there were significant differences in Δpeak2 and ΔRBF2 between the groups. The Δpeak1 and ΔRBF2 showed good prediction (AUC 0.798-0.820, p ≤ 0.02) after the first cycle of NAC. When the cut-off value was 0.115, the ΔRBF2 had the highest diagnostic accuracy and the maximum NPV. Quantitative TIC parameters could be effectively used to evaluate early response to NAC in advanced breast cancer.

Quantification of spatial pharmacogene expression heterogeneity in breast tumors.

Chemotherapeutic drug concentrations vary across different regions of tumors and this is thought to be involved in development of chemotherapy resistance. Insufficient drug delivery to some regions of the tumor may be due to spatial differences in expression of genes involved in the disposition, transport, and detoxification of drugs (pharmacogenes). Therefore, in this study, we analyzed the spatial expression of 286 pharmacogenes in six breast cancer tissues using the recently developed Visium spatial transcriptomics platform to (1) determine if these pharmacogenes are expressed heterogeneously across tumor tissue and (2) to determine which pharmacogenes have the most spatial expression heterogeneity. The spatial transcriptomics technology sequences the transcriptome of 55 um diameter barcoded sections (spots) across a tissue sample. We analyzed spatial gene expression profiles of four biobank-sourced breast tumor samples in addition to two breast tumor sample datasets from 10× Genomics. We define heterogeneity as the interquartile range of read counts. Collectively, we identified 8887 spots in tumor regions, 3814 in stroma, 44 in lymphocytes, and 116 in normal regions based on pathologist annotation of the tissues. We showed statistically significant differences in expression of pharmacogenes in tumor regions compared to surrounding non-tumor regions. We also observed that the most heterogeneously expressed genes within tumor regions were involved in reactive oxygen species (ROS)handling and detoxification mechanisms. GPX4, GSTP1, MGST3, SOD1, CYP4Z1, CYB5R3, GSTK1, and NAT1 showed the most heterogeneous expression within tumor regions. The heterogeneous expression of these pharmacogenes may have important implications for cancer therapy due to their ability to impact drug distribution and efficacy throughout the tumor. Our results suggest that chemoresistance caused by expression of GPX4, GSTP1, MGST3, and SOD1 may be intrinsic, not acquired, since the heterogeneity is not specific to chemotherapy-treated samples or cell type. Additionally, we identified candidate chemoresistance pharmacogenes that can be further tested through focused follow-up studies.

Diversity in tumor territory of meningioma: Protein expression in vascular endothelial growth factor and epidermal growth factor

Background: Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are involved in tumor development and progression. But, the classified-based data of protein expression (PE) in meningiomas is unavailable. Therefore, we aimed to explore the PE of VEGF and EGF in meningiomas by considering evolutionary strategy and the regional tumor-based assay. Methods: PE was assayed using immunofluorescence (IF) within the peripheral, central, and basal sections of four meningioma tumors, and a lung metastatic brain tumor as a positive control. Results: Diverse characteristics and harmonic cross-talk in the individual sections and between different tumor sections were traced. The mode of PE was puzzling and personalized issue. Co-expression had a key impact on tumor evolution and diverse PE profiles led to draw the heterogenic classification, as the personalized/complementary insight in the functional behavior of VEGF and EGF. D1853N polymorphism of ATM gene was mosaics in two patients with meningiomas. Conclusion: The classified heterogeneity, harmonic co-expression, and diverse functional information in different regions of tumors may lead to predict the aggressiveness mode of tumors as a translational insight to the clinical managements including therapy in brain tumors.

A Dynamic Model of Immune Responses to Antigen Presentation Predicts Different Regions of Tumor or Pathogen Elimination

The immune system must discriminate between agents of disease and an organism's healthy cells. While the identification of an antigen as self/non-self is critically important, the dynamic features of antigen presentation may also determine the immune system's response. Here, we use a simple mathematical model of immune activation to explore the idea of antigen discrimination through dynamics. We propose that antigen presentation is coupled to two nodes, one regulatory and one effecting the immune response, through an incoherent feedforward loop and repressive feedback. This circuit would allow the immune system to effectively estimate the increase of antigens with respect to time, a key determinant of immune reactivity invivo. Our model makes the prediction that tumors growing at specific rates evade the immune system despite the continuous presence of antigens indicating disease, a phenomenon closely related to clinically observed "two-zone tolerance." Finally, we discuss a plausible biological instantiation of our circuit using combinations of regulatory and effector Tcells.

The toolbox of designing nanoparticles for tumors.

Nanoparticles (NPs) show great promise in the treatment of a wide range of diseases, which provides advantages and offers a new prospect for tumor detection, prevention and treatment. In order to eradicate the cancer cell, the NPs need to flow to different regions of tumors via blood vessels, and then penetrate through the interstitial space to reach the target cells. However, the environment and physiological characteristics in tumor tissues are different from that in normal ones, mainly in the irregular blood vessels, the lack of lymphatic network, low pH, hypoxia, immune function and so on. Meanwhile, the differences also exist among different tumor tissues. To achieve the optimal therapeutic effect, the NPs should be carefully designed by considering the therapeutic application, the target site and the route of administration. This review shows a variety of barriers in the tumor tissues, and provides a toolbox of designing the NPs for tumor treatment. In particular, the particle size, shape and surface chemistry, and the NPs in preclinical and clinical stage use have been discussed.

Intratumoral Modeling of Gefitinib Pharmacokinetics and Pharmacodynamics in an Orthotopic Mouse Model of Glioblastoma

Like many solid tumors, glioblastomas are characterized by intratumoral biologic heterogeneity that may contribute to a variable distribution of drugs and their associated pharmacodynamic responses, such that the standard pharmacokinetic approaches based on analysis of whole-tumor homogenates may be inaccurate. To address this aspect of tumor pharmacology, we analyzed intratumoral pharmacokinetic/pharmacodynamic characteristics of the EGFR inhibitor gefitinib in mice with intracerebral tumors and developed corresponding mathematical models. Following a single oral dose of gefitinib (50 or 150 mg/kg), tumors were processed at selected times according to a novel brain tumor sectioning protocol that generated serial samples to measure gefitinib concentrations, phosphorylated extracellular signal-regulated kinase (pERK), and immunohistochemistry in 4 different regions of tumors. Notably, we observed up to 3-fold variations in intratumoral concentrations of gefitinib, but only up to half this variability in pERK levels. As we observed a similar degree of variation in the immunohistochemical index termed the microvessel pericyte index (MPI), a measure of permeability in the blood-brain barrier, we used MPI in a hybrid physiologically-based pharmacokinetic (PBPK) model to account for regional changes in drug distribution that were observed. Subsequently, the PBPK models were linked to a pharmacodynamic model that could account for the variability observed in pERK levels. Together, our tumor sectioning protocol enabled integration of the intratumoral pharmacokinetic/pharmacodynamic variability of gefitinib and immunohistochemical indices followed by the construction of a predictive PBPK/pharmacodynamic model. These types of models offer a mechanistic basis to understand tumor heterogeneity as it impacts the activity of anticancer drugs.

Combined imaging biomarkers for therapy evaluation in glioblastoma multiforme: correlating sodium MRI and F-18 FLT PET on a voxel-wise basis

We evaluate novel magnetic resonance imaging (MRI) and positron emission tomography (PET) quantitative imaging biomarkers and associated multimodality, serial-time-point analysis methodologies, with the ultimate aim of providing clinically feasible, predictive measures for early assessment of response to cancer therapy. A focus of this work is method development and an investigation of the relationship between the information content of the two modalities. Imaging studies were conducted on subjects who were enrolled in glioblastoma multiforme (GBM) therapeutic clinical trials. Data were acquired, analyzed and displayed using methods that could be adapted for clinical use. Subjects underwent dynamic [18F]fluorothymidine (F-18 FLT) PET, sodium (23Na) MRI and 3-T structural MRI scans at baseline (before initiation of therapy), at an early time point after beginning therapy and at a late follow-up time point after therapy. Sodium MRI and F-18 FLT PET images were registered to the structural MRI. F-18 FLT PET tracer distribution volumes and sodium MRI concentrations were calculated on a voxel-wise basis to address the heterogeneity of tumor physiology. Changes in, and differences between, these quantities as a function of scan timing were tracked.While both modalities independently show a change in tissue status as a function of scan time point, results illustrate that the two modalities may provide complementary information regarding tumor progression and response. Additionally, tumor status changes were found to vary in different regions of tumor. The degree to which these methods are useful for GBM therapy response assessment and particularly for differentiating true progression from pseudoprogression requires additional patient data and correlation of these imaging biomarker changes with clinical outcome.

Induction of DNA Hypomethylation by Tumor Hypoxia

In cancer the extensive methylation found in the bulk of chromatin is reduced, while the normally unmethylated CpG islands become hypermethylated. Regions of solid tumors are transiently and/or chronically exposed to ischemia (hypoxia) and reperfusion, conditions known to contribute to cancer progression. We hypothesized that hypoxic microenvironment may influence local epigenetic alterations, leading to inappropriate silencing and re-awakening of genes involved in cancer. We cultured human colorectal and melanoma cancer cell lines under severe hypoxic conditions, and examined their levels of global methylation using HPLC to quantify 5-methylcytosine (5-mC), and found that hypoxia induced losses of global methylation. This was more extensive in normal human fibroblasts than cancer cell lines. Cell lines from metastatic colorectal carcinoma or malignant melanoma were found to be markedly more hypomethylated than cell lines from their respective primary lesions, but they did not show further reduction of 5-mC levels under hypoxic conditions. To explore these epigenetic changes in vivo, we established xenografts of the same cancer cells in immune deficient mice. We used Hypoxyprobe™ to assess the magnitude of tissue hypoxia, and immunostaining for 5-mC to evaluate DNA methylation status in cells from different regions of tumors. We found an inverse relationship between the presence of extensive tumor hypoxia and the incidence of methylation, and a reduction of 5-mC in xenografts compared to the levels seen in the same cancer cell lines in vitro, verifying that methylation patterns are also modulated by hypoxia in vivo. This suggests that epigenetic events in solid tumors may be modulated by microenvironmental conditions such as hypoxia.

Functional genomics guided with MR imaging: mouse tumor model study.

To gain a better understanding of gene expression patterns in tumors, the authors used contrast material-enhanced magnetic resonance (MR) imaging to noninvasively characterize regions within the same tumor to provide a correlate for genomic analysis. Gene expression profiles of samples from a mouse tumor model obtained from contrast-enhanced and nonenhanced regions within the same tumor were compared with MR imaging and functional genomics. From these samples, 11000 genes were analyzed: 10 genes were up-regulated in the contrast-enhanced areas, and one gene was up-regulated in the nonenhanced regions. Several of these genes encode extracellular matrix proteins. Findings in this study demonstrate that MR imaging can serve as a powerful noninvasive tool for characterizing different regions of tumors to guide genomic analysis with high spatial and temporal resolution.

Typical and atypical MR imaging features of intracranial epidermoid tumors.

We categorized the MR imaging characteristics of intracranial epidermoid tumors. MR images from 23 cases of intracranial epidermoid tumors were reviewed retrospectively. Signal intensities of tumor relative to surrounding structures were noted, as were the internal architecture of the tumors and the presence and degree of hydrocephalus. Seventeen (74%) of 23 cases of intracranial epidermoid tumors were revealed as slightly hyperintense relative to CSF on T1-weighted MR images. Nineteen (95%) of 20 cases were hyperintense relative to CSF on proton density-weighted MR images. Fifteen (65%) of 23 cases were isointense to CSF on T2-weighted MR images, whereas the remaining eight cases (35%) were hyperintense to CSF on T2-weighted MR images. One (4%) of 23 cases showed signal intensity that was isointense to CSF on all pulse sequences. Fifteen (65%) of 23 cases showed heterogeneous signal characteristics on either T1-weighted or proton density-weighted MR images, or both. Eight (35%) of 23 cases showed a rim of hyperintensity on proton density-weighted MR images. Five (33%) of the 15 cases that received gadolinium showed rim enhancement. Five (22%) of 23 cases were multilocular, with different regions of tumors showing highly variable imaging characteristics. Two (9%) of 23 cases showed high signal intensity on T2-weighted MR images in the adjacent brain parenchyma. Two (9%) of 23 cases showed mild hydrocephalus. Six (43%) of 14 tumors that either originated in or secondarily involved the cerebellopontine angle also extended into the ipsilateral Meckel's cave. On T1-, proton density-, and T2-weighted MR images intracranial epidermoid tumors usually showed heterogeneous signal intensity that was hyperintense to CSF. On all spin-echo pulse sequences epidermoid tumors with signal characteristics isointense to CSF were unusual. Hydrocephalus, even in the setting of marked displacement and compression of the brainstem, was not usually seen on MR imaging. Meckel's cave was often involved secondarily with epidermoid tumors that involved the cerebellopontine angle.

Heterogeneity of squamous cell carcinomas of the head and neck--analysis of tumor biologic factors and proliferation rates.

Specimens obtained from five different tumor regions in 12 patients who underwent surgery for squamous cell carcinoma (SCC) of the oropharynx were examined. The evaluation of each biopsy included quantitative DNA measurements based on image analysis, immunohistochemical assessment of proliferations markers (i.e., Ki67-MIB1, proliferating cell nuclear antigen [PCNA]), and morphological tumor-front grading. From single cell measurements, several DNA indices were derived which are known to reflect tumor aneuploidy. The results revealed a marked variation of proliferation and cellular differentiation in different regions of tumors and a wide intraindividual variation between particular tumors for all markers examined. There was good correlation between DNA data and proliferative cell fractions (Ki67 score, PCNA score). With the use of diagrams, three-dimensional distribution of proliferation rates and markers reflecting tumor aggressiveness within each tumor was obtained. The results confirmed previous clinical and histological observations that SCCs of the oropharynx are heterogeneous tumors. One might expect that the regions with increased proliferation and aggressiveness may predict the location of possible tumor recurrence.

Lysosomes, Lysosomal Enzymes, and Cancer

Lysosomes are membrane-enclosed cytoplasmic organelles, which posses an acidic interior that contains many hydrolytic enzymes. Their major function is in the the degradation of macromolecules, which may be cellular or foreign in origin. This chapter discusses the properties of lysosomes and their enzymes that are relevant to malignancy. Lysosomal hydrolases are synthesized and glycosylated in the rough endoplasmic reticulum. Lysosomes play an important role in the malignant process. Aspects of carcinogenesis, invasion and metastasis, and shrinkage of neoplasms in response to therapy have all been attributed to lysosomes or their products. Lysosomes can be studied by several methods, such as by ultracentrifugation isolation, enzyme activity assay, histochemical techniques, and electron microscopy. The activity of lysosomal enzymes in human tumors is compared to the normal tissue of origin. Elevation in the serum level of lysosomal enzymes is reported in both cancer patients and tumor-bearing animals. Lysosomal enzyme activity is estimated in different regions of tumors. Lysosomal enzymes are associated with invasiveness and metastatic potential in some experimental tumors. Lysosomes play a role in the uptake, processing, or efflux of some cytotoxic agents and might provide mechanisms leading to some forms of drug resistance.

Heterogeneity of heat response in murine, canine and human tumors: Influence on predictive assays

The heterogeneity of response to hyperthermia of cells taken from different regions of tumors was tested in a model tumor system (RIF-1) in the mouse and in specimens from spontaneous tumors taken from dogs and humans at the time of surgical resection. Cell survival was assayed by clonogenic survival in the murine tumor and by dansyl lysine staining in tumors from all three species. Using survival as an endpoint, it was found that the extent of heterogeneity depended on the temperature to which the tumor was heated and the duration of exposure. By increasing either of these factors, the coefficient of variation was increased. The large heterogeneity seen after in vivo heating could not be explained entirely by inhomogeneous heating within the tumor as evidenced by temperature mapping. It is concluded that other microenvironmental factors such as blood flow, pH, 02, and nutrient supply may cause variations in the heat response of the tumor cells in vivo. Little, if any, evidence of cellular heterogeneity was evident for all three species when comparisons were made between samples of 100–200 mg. The canine and human tumors were considerably more heat resistant when dansyl lysine was used as an endpoint. In the RIF-1 tumors, heterogeneity of heat response was greater after in vitro heating than after in vivo heating when small biopsy samples (10–20 mg) were taken, suggesting that some cellular heterogeneity was present.