Effect of nonsteroidal anti-inflammatory drugs (aspirin and naproxen) on inflammation-associated proteomic profiles in mouse plasma and prostate during TMPRSS2-ERG (fusion)-driven prostate carcinogenesis.

Recent preclinical studies have shown that the intake of nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and naproxen could be an effective intervention strategy against TMPRSS2-ERG fusion-driven prostate tumorigenesis. Herein, as a follow-up mechanistic study, employing TMPRSS2-ERG (fusion) positive tumors and plasma from TMPRSS2-ERG. Ptenflox/flox mice, we profiled the stage specific proteomic changes (focused on inflammatory circulating and prostate tissue/tumor-specific cytokines, chemokines, and growth factors/growth signaling-associated molecules) that contribute to prostate cancer (PCa) growth and progression in the TMPRSS2-ERG fusion-driven mouse model of tumorigenesis. In addition, the association of the protective effects of NSAIDs (aspirin 1400 ppm and naproxen 400 ppm) with the modulation of these specific molecular pathways was determined. A sandwich Elisa based membrane array-proteome profiler identifying 111 distinct signaling molecules was employed. Overall, the plasma and prostate tissue sample analyses identified 54 significant and differentially expressed cytokines, chemokines, and growth factors/growth signaling-associated molecules between PCa afflicted mice (TMPRSS2-ERG. Ptenflox/flox, age-matched noncancerous controls, NSAIDs-supplemented and no-drug controls). Bioinformatic analysis of the array outcomes indicated that the protective effect of NSAIDs was associated with reduced expression of (a) tumor promoting inflammatory molecules (M-CSF, IL-33, CCL22, CCL12, CX3CL1, CHI3L1, and CD93), (b) growth factors- growth signaling-associated molecules (Chemerin, FGF acidic, Flt-3 ligand, IGFBP-5, and PEDF), and (c) tumor microenvironment/stromal remodeling proteins MMP2 and MMP9. Overall, our findings corroborate the pathological findings that protective effects of NSAIDs in TMPSS2-ERG fusion-driven prostate tumorigenesis are associated with antiproliferative and anti-inflammatory effects and possible modulation of the immune cell enriched microenvironment.

Longitudinal Bottom-Up Proteomics of Serum, Serum Extracellular Vesicles, and Cerebrospinal Fluid Reveals Candidate Biomarkers for Early Detection of Glioblastoma in a Murine Model.

Glioblastoma Multiforme (GBM) is a brain tumor with a poor prognosis and low survival rates. GBM is diagnosed at an advanced stage, so little information is available on the early stage of the disease and few improvements have been made for earlier diagnosis. Longitudinal murine models are a promising platform for biomarker discovery as they allow access to the early stages of the disease. Nevertheless, their use in proteomics has been limited owing to the low sample amount that can be collected at each longitudinal time point. Here we used optimized microproteomics workflows to investigate longitudinal changes in the protein profile of serum, serum small extracellular vesicles (sEVs), and cerebrospinal fluid (CSF) in a GBM murine model. Baseline, pre-symptomatic, and symptomatic tumor stages were determined using non-invasive motor tests. Forty-four proteins displayed significant differences in signal intensities during GBM progression. Dysregulated proteins are involved in cell motility, cell growth, and angiogenesis. Most of the dysregulated proteins already exhibited a difference from baseline at the pre-symptomatic stage of the disease, suggesting that early effects of GBM might be detectable before symptom onset.

Ethyl acrylate (EA) exposure and thyroid carcinogenicity in rats and mice with relevance to human health.

Ethyl acrylate (EA) was classified by IARC as a Group-2B Carcinogen based, in part, on data suggesting increased incidence of thyroid neoplasia in rats and mice exposed chronically to EA vapors. We examined chronic exposure of rats and mice to EA vapors, evaluated the data on the incidence of thyroid follicular neoplasia, and determined the relevance of thyroid tumors to human health risk. The data revealed a small statistically significant increase in thyroid tumors in EA-exposed male rats and mice. The tumor incidences were within the range of historical controls and were not consistently dose-dependent. Most thyroid tumors in exposed animals were benign. Chronic exposure of EA to rats and mice (drinking water or gavage) and dogs (capsules) had no evidence of thyroid neoplasia. Results from chronic studies, in vivo and in vitro data, and ToxCastTM/Tox 21 HTPS did not support genotoxic/mutagenic potential for EA. This suggests that the associations between EA exposure and thyroid neoplasia represent chance or random observations rather than a compound-mediated effect. Due to species-specific physiological differences, the hypothalamic-pituitary-thyroid axis of rodents is more sensitive to endocrine disruptive chemicals than that of humans which further suggests that findings in rodents have questionable relevance to human health.

Enhancement of innate and adaptive anti-tumor immunity by serum obtained from vascular photodynamic therapy-cured BALB/c mouse.

Photodynamic therapy (PDT) is a clinically approved treatment for various types of cancer. Besides killing the tumor cells directly, PDT has also been reported to trigger anti-tumor immunity. In our previous study, BAM-SiPc-based PDT was shown to induce immunogenic cell death on CT26 murine colon tumor cells in vitro. Using the BALB/c mouse animal model and a vascular-PDT (VPDT) approach, it could also eradicate tumor in ∼ 70% of tumor-bearing mice and elicit an anti-tumor immune response. In the present study, the serum obtained from the VPDT-cured mice was studied and found to possess various immunomodulatory properties. In in vitro studies, it stimulated cytokine secretions of IL-6 and C-X-C motif chemokine ligands 1-3 in CT26 cells through the NF-κB and MAPK pathways. The complement protein C5a boosted in the serum was shown to be involved in the process. The serum also induced calreticulin exposure on CT26 cells and activated dendritic cells. It contained CT26-targeting antibodies which, through the Fc region, induced macrophage engulfment of the tumor cells. In in vivo studies, inoculation of the serum-treated CT26 cells to mice demonstrated a retarded tumor growth with leukocytes, particularly T cells, attracted to the tumor site. In addition, the VPDT-cured mice showed different degrees of resistance against challenge of other types of murine tumor cells, for example, the breast tumor 4T1 and EMT6 cells.

C3 Drives Inflammatory Skin Carcinogenesis Independently of C5.

Nonmelanoma skin cancer such as cutaneous squamous cell carcinoma (cSCC) is the most common form of cancer and can occur as a consequence of DNA damage to the epithelium by UVR or chemical carcinogens. There is growing evidence that the complement system is involved in cancer immune surveillance; however, its role in cSCC remains unclear. Here, we show that complement genes are expressed in tissue from patients with cSCC, and C3 activation fragments are present in cSCC biopsies, indicating complement activation. Using a range of complement-deficient mice in a two-stage mouse model of chemically-induced cSCC, where a subclinical dose of 7,12-dimethylbenz[a]anthracene causes oncogenic mutations in epithelial cells and 12-O-tetradecanoylphorbol-13-acetate promotes the outgrowth of these cells, we found that C3-deficient mice displayed a significantly reduced tumor burden, whereas an opposite phenotype was observed in mice lacking C5aR1, C5aR2, and C3a receptor. In addition, in mice unable to form the membrane attack complex, the tumor progression was unaltered. C3 deficiency did not affect the cancer response to 7,12-dimethylbenz[a]anthracene treatment alone but reduced the epidermal hyperplasia during 12-O-tetradecanoylphorbol-13-acetate-induced inflammation. Collectively, these data indicate that C3 drives tumorigenesis during chronic skin inflammation, independently of the downstream generation of C5a or membrane attack complex.

Green nanogold activity in experimental breast carcinoma in vivo.

BACKGROUND: Over the past few years, fabrication of nanoparticles (NPs) has been deployed widely in technologies and many concerns have emerged about the hazardous effect on human health after NPs exposure. OBJECTIVE: Green synthesis of gold NPs (AuNPs) and assessment of their activity in 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer mouse model. METHODS: Chloroauric acid (HAuCl4) was used in formation of AuNPs with the help of Curcuma longa as aqueous reducing extract and stabilizing agent at room temperature. Formed NPs were characterized with UV-Vis spectrometry, Fourier-transform infrared spectroscopy (FTIR), Zetasizer measurement, Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). Virgin female albino mice with DMBA-induced breast cancer were treated with formed AuNPs for 5 consecutive days and were dissected after 28 days of the beginning of treatment. RESULTS: UV-Vis spectrometry showed absorbance maximum peak at 530 nm for formed AuNPs, FTIR confirmed formation of plant extract layer around formed NPs; zetasizer measurement revealed 278.2 nm as an average size of produced NPs; SEM and TEM approved formation of monodisperse spherical AuNPs. Biochemical analysis of untreated breast cancer group revealed marked changes in liver and kidney functions manifested by raised activity levels of alanine transaminase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine. Whereas, the treated group with AuNPs post-breast cancer induction displayed reduction in the activities (of ALT, AST and creatinine), while the BUN activity level was raised. Histopathological examination showed heavy incidence of tumor foci in the breast and lymph nodes belonged to the untreated breast cancer group confirmed with intense response to Ki-67 antibodies. While the treated group with AuNPs post-breast cancer induction showed degenerated tumor foci in the breast and lymph nodes with weak response to Ki-67 antibodies. CONCLUSION: AuNPs were successfully synthesized using HAuCl4 and C. longa extract confirmed their ability to control DMBA-induced breast cancer in virgin female Swiss albino mice.

Multimerization through Pegylation Improves Pharmacokinetic Properties of scFv Fragments of GD2-Specific Antibodies.

Antigen-binding fragments of antibodies specific to the tumor-associated ganglioside GD2 are well poised to play a substantial role in modern GD2-targeted cancer therapies, however, rapid elimination from the body and reduced affinity compared to full-length antibodies limit their therapeutic potential. In this study, scFv fragments of GD2-specific antibodies 14.18 were produced in a mammalian expression system that specifically bind to ganglioside GD2, followed by site-directed pegylation to generate mono-, di-, and tetra-scFv fragments. Fractionated pegylated dimers and tetramers of scFv fragments showed significant increase of the binding to GD2 which was not accompanied by cross-reactivity with other gangliosides. Pegylated multimeric di-scFvs and tetra-scFvs exhibited cytotoxic effects in GD2-positive tumor cells, while their circulation time in blood significantly increased compared with monomeric antibody fragments. We also demonstrated a more efficient tumor uptake of the multimers in a syngeneic GD2-positive mouse cancer model. The findings of this study provide the rationale for improving therapeutic characteristics of GD2-specific antibody fragments by multimerization and propose a strategy to generate such molecules. On the basis of multimeric antibody fragments, bispecific antibodies and conjugates with cytotoxic drugs or radioactive isotopes may be developed that will possess improved pharmacokinetic and pharmacodynamic properties.

Simple and robust polymer-based sensor for rapid cancer detection using serum.

We report a polymer-based sensor that rapidly detects cancer based on changes in serum protein levels. Using three ratiometric fluorescence outputs, this simple system identifies early stage and metastatic lung cancer with a high level of accuracy exceeding many biomarker-based assays, making it an attractive strategy for point-of-care testing.

The diagnostic efficacy of circulating miRNAs in monitoring the early development of colitis-induced colorectal cancer.

Early detection of colorectal cancer and monitoring the progress in colon carcinogenesis stages is essential to reduce mortality. Therefore, there is continuous search for noninvasive biomarkers with high stability and good sensitivity and specificity. miRNAs have attracted attention as promising biomarkers as they are stably expressed in circulation. The aim of our study is to evaluate the aberrant expression of circulating miRNAs during the stepwise progress of colitis-associated colon cancer. This was accomplished through assessing the expression levels of five miRNAs (miR-141, miR-15b, miR-17-3p, miR-21, and miR-29a) in serum and their corresponding tissue samples through the different cycles of colorectal carcinogenesis cascade using the azoxymethane/dextran sulfate sodium murine model. We also compared the diagnostic performance of these selected miRNAs with the conventional tumor biomarkers CEA and CA 19-9. The results of our study revealed that the expression levels of those miRNAs were dynamically changing in accordance with the tumor development state. Moreover, their aberrant expression in serum was statistically correlated with that in tissue. Our data also revealed that serum miR-15b, miR-21, and miR-29a showed the best performance in terms of diagnostic power. Our findings highlight the efficiency of these circulating miRNAs not only for early diagnostics purposes, but also for monitoring progress in the colorectal carcinogenesis process, and therefore encouraging integrating these noninvasive biomarkers into the clinical diagnostic settings beside the traditional diagnostic markers for accurate screening of the early progress of colon carcinogenesis.

Conserved serum protein biomarkers associated with growing early colorectal adenomas.

A major challenge for the reduction of colon cancer is to detect patients carrying high-risk premalignant adenomas with minimally invasive testing. As one step, we have addressed the feasibility of detecting protein signals in the serum of patients carrying an adenoma as small as 6-9 mm in maximum linear dimension. Serum protein biomarkers, discovered in two animal models of early colonic adenomagenesis, were studied in patients using quantitative mass-spectrometric assays. One cohort included patients bearing adenomas known to be growing on the basis of longitudinal computed tomographic colonography. The other cohort, screened by optical colonoscopy, included both patients free of adenomas and patients bearing adenomas whose risk status was judged by histopathology. The markers F5, ITIH4, LRG1, and VTN were each elevated both in this patient study and in the studies of the Pirc rat model. The quantitative study in the Pirc rat model had demonstrated that the elevated level of each of these markers is correlated with the number of colonic adenomas. However, the levels of these markers in patients were not significantly correlated with the total adenoma volume. Postpolypectomy blood samples demonstrated that the elevated levels of these four conserved markers persisted after polypectomy. Two additional serum markers rapidly renormalized after polypectomy: growth-associated CRP levels were enhanced only with high-risk adenomas, while PI16 levels, not associated with growth, were reduced regardless of risk status. We discuss biological hypotheses to account for these observations, and ways for these signals to contribute to the prevention of colon cancer.

Nucleic acid hybridization on an electrically reconfigurable network of gold-coated magnetic nanoparticles enables microRNA detection in blood.

There is intense interest in quantifying the levels of microRNA because of its importance as a blood-borne biomarker. The challenge has been to develop methods that can monitor microRNA expression both over broad concentration ranges and in ultralow amounts directly in a patient's blood. Here, we show that, through electric-field-induced reconfiguration of a network of gold-coated magnetic nanoparticles modified by probe DNA (DNA-Au@MNPs), it is possible to create a highly sensitive sensor for direct analysis of nucleic acids in samples as complex as whole blood. The sensor is the first to be able to detect concentrations of microRNA from 10 aM to 1 nM in unprocessed blood samples. It can distinguish small variations in microRNA concentrations in blood samples of mice with growing tumours. The ultrasensitive and direct detection of microRNA using an electrically reconfigurable DNA-Au@MNPs network makes the reported device a promising tool for cancer diagnostics.

NMR-based metabolic profiling of urine, serum, fecal, and pancreatic tissue samples from the Ptf1a-Cre; LSL-KrasG12D transgenic mouse model of pancreatic cancer.

Pancreatic cancer is the third leading cause of cancer deaths in the United States with more than 53,000 expected to be diagnosed with the disease in 2018. The median survival time after diagnosis is four to six months. The poor survival statistics are due in part to the fact that pancreatic cancer is typically asymptomatic until it reaches advanced stages of the disease. Although surgical resection provides the best chance of survival, pancreatic cancer is rarely detected when surgery is still possible due, in part, to lack of effective biomarkers for early detection. The goal of the research reported here was to determine if it was possible to identify metabolic biomarkers for detection of pre-cancerous pancreatic intraepithelial neoplasia (PanIN) that precede pancreatic adenocarcinoma. The transgenic Ptf1a-Cre; LSL-KrasG12D mouse strain was used as a model of pancreatic cancer progression. Nuclear magnetic resonance (NMR) spectroscopy was employed to compare metabolic profiles of urine, sera, fecal extracts, and pancreatic tissue extracts collected from control and study mice aged 5, 11, and 15 months, including 47 mice with tumors. We were able to identify the following potential biomarkers: decreased 3-indoxylsulfate, benzoate and citrate in urine, decreased glucose, choline, and lactate in blood, and decreased phenylalanine and benzoate and increased acetoin in fecal extracts. Potential biomarkers were validated by p-values, PLS-DA VIP scores, and accuracies based on area under ROC curve analyses. Essentially, all of the metabolic profiling changes could be explained as being associated with the consequences of bicarbonate wasting caused by a complete substitution of the normal pancreatic acinar tissue by tissue entirely composed of PanIN. Given the nature of the mouse model used here, our results indicate that it may be possible to use NMR-based metabolic profiling to identify biomarkers for detection of precancerous PanIN that immediately precede pancreatic cancer.

Continuous low-dose infusion of patupilone increases the therapeutic index in mouse and rat tumour models.

Patupilone is a microtubule-targeted cytotoxic agent with clinical efficacy, but causes diarrhoea in more than 80% of patients. The efficacy and tolerability of patupilone delivered continuously by subcutaneous (s.c.) mini-pumps [(mini-pump dose (MPD)] or by intravenous bolus administration [intravenous bolus dose (IVBD)] were compared preclinically to determine whether the therapeutic index could be improved. The antiproliferative potency in vitro of patupilone was determined by measuring total cell protein. Tumours were grown s.c. in rats (A15) or nude mice (KB31, KB8511) or intracranially in nude mice (NCI-H460-Luc). Efficacy was monitored by measuring tumour volumes, bioluminescence or survival. Toxicity was monitored by body weight and/or diarrhoea. Total drug levels in blood, plasma, tissues or dialysates were quantified ex-vivo by liquid chromatography-mass spectroscopy/mass spectroscopy. Patupilone was potent in vitro with GI50s of 0.24-0.28 nmol/l and GI90s of 0.46-1.64 nmol/l. In rats, a single IVBD of patupilone dose dependently inhibited the growth of A15 tumours, but also caused dose-dependent body weight loss and diarrhoea, whereas MPD achieved similar efficacy, but no toxicity. In mice, MPD showed efficacy similar to that of IVBD against KB31 and KB8511 tumours, but with reduced toxicity. In a mouse intracranial tumour model, IVBD was more efficacious than MPD, consistent with patupilone concentrations in the brain. MPD provided constant plasma levels, whereas IVBD had very high C0/Cmin ratios of 70-280 (rat) or 8000 (mouse) over the dosing cycle. Overall, the correlation of plasma and tumour levels with response indicated that a Cave of at least GI90 led to tumour stasis. Continuous low concentrations of patupilone by MPD increased the therapeutic index in s.c. rodent tumour models compared with IVBD by maintaining efficacy, but reducing toxicity.

Prediction of Tumor-to-Plasma Ratios of Basic Compounds in Subcutaneous Xenograft Mouse Models.

BACKGROUND: Predicting target site drug concentrations is of key importance for rank ordering compounds before proceeding to chronic pharmacodynamic models. We propose generic tumor-specific correlation-based regression equations to predict tumor-to-plasma ratios (tumor-Kps) in slow- and fast-growing xenograft mouse models. METHODS: Disposition of 14 basic small molecules was investigated extensively in mouse plasma, tissues and tumors after a single oral dose administration. Linear correlation was assessed and compared between tumor-Kp and normal tissue-to-plasma ratio (tissue-Kps) separately for each tumor xenograft. The developed regression equations were validated by leave-one-out cross-validation (LOOCV) method. RESULT: Both slow- and fast-growing tumor-Kps showed good correlation (r 2 ≥ 0.7) with majority of the normal tissue-Kps. Substantial difference was observed in the slopes of developed equations between two xenografts, which was in line with observed difference in tumor distribution. The linear correlations between tumor-Kp and skin- or spleen-Kp were within the acceptable statistical criteria (LOOCV) across xenografts and the class of compounds evaluated. Since > 70% of tumor-Kps from the test data sets were predicted within a factor of twofold for both slow- and fast-growing xenograft mouse models, the results validate the applicability of the developed equations across xenografts. CONCLUSION: Tumor-specific correlation-based regression equations were developed and their applicability was adequately validated across xenografts. These equations could be successfully translated to predict tumor concentrations in order to preclude experimental tumor-Kp determination.

Impact of protamine I on colon cancer proliferation, invasion, migration, diagnosis and prognosis.

This paper investigates protamine I (PRM1) expression and its effects on proliferation, invasion and migration of colon cancer cells as well as its function in clinical diagnosis and prognosis. Gene chips were used to screen differentially expressed genes. PRM1 expression was detected by Western blotting and quantitative real time-polymerase chain reaction (qRT-PCR). Hematoxylin and eosin (HE) staining and immunohistochemistry were utilized to compare the expression of PRM1 from multiple differentiation levels of colon cancer tissues. Cell viability, cell apoptosis and cell cycle were tested using the MTT assay and flow cytometry. Cell invasion and migration capability were tested using the Transwell assay and wound healing. In vivo effects of PRM1 on colon cancer were explored using a xenograft model. PRM1 expression in serum was detected by enzyme-linked immunosorbent assay (ELISA). The expression level of PRM1 was significantly higher in colon cancer tissues and the staining degree of PRM1 in poorly-differentiated was stronger. pcDNA3.1-PRM1 decreased cell apoptosis while it increased the proliferation, cell invasion and migration. The si-PRM1 group displayed an opposite tendency. The serum PRM1 level was significantly higher and could serve as a diagnostic biomarker for colon cancer.

Infection with Opisthorchis felineus induces intraepithelial neoplasia of the biliary tract in a rodent model.

The liver fluke Opisthorchis felineus is a member of the triad of epidemiologically relevant species of the trematode family Opisthorchiidae, and the causative agent of opisthorchiasis felinea over an extensive range that spans regions of Eurasia. The International Agency for Research on Cancer classifies the infection with the liver flukes Opisthorchis viverrini and Clonorchis sinensis as group 1 agents and a major risk factor for cholangiocarcinoma. However, the carcinogenic potential of the infection with O. felineus is less clear. Here, we present findings that support the inclusion of O. felineus in the Group 1 list of biological carcinogens. Two discrete lines of evidence support the notion that infection with this liver fluke is carcinogenic. First, novel oxysterol-like metabolites detected by liquid chromatography-mass spectroscopy in the egg and adult developmental stages of O. felineus, and in bile, sera, and urine of liver fluke-infected hamsters exhibited marked similarity to oxysterol-like molecules known from O. viverrini. Numerous oxysterols and related DNA-adducts detected in the liver fluke eggs and in bile from infected hamsters suggested that infection-associated oxysterols induced chromosomal lesions in host cells. Second, histological analysis of liver sections from hamsters infected with O. felineus confirmed portal area enlargement, inflammation with severe periductal fibrosis and changes in the epithelium of the biliary tract characterized as biliary intraepithelial neoplasia, BilIN. The consonance of these biochemical and histopathological changes revealed that O. felineus infection in this rodent model induced precancerous lesions conducive to malignancy.

[Effect of iron nanoparticles on free radical oxidation process in blood of rats with Pliss lymphosarcoma]. / Vliianie nanochastits zheleza na pokazateli svobodnoradikal'nogo okisleniia v krovi krys s limfosarkomoi Plissa.

The use of metal nanoparticles (NPs) for cancer treatment requires careful examination of their biological effects. The aim of this study was to determine parameters of oxidative processes in the blood of tumor-bearing animals treated with metallic iron NPs only. The markers of antioxidant status and accumulation of lipid peroxidation products were measured in erythrocytes and blood plasma of rats with Pliss lymphosarcoma (PLS) and intact rats. PLS animals were treated eight times with iron NPs (at a dose of 1.25 mg/kg bw (main group), rats of the control group received saline (0.3 ml). In control animals, an increase in malondialdehyde (MDA) was observed in red blood cells (RBC) by 45%; this was accompanied by compensatory increase in reduced glutathione (GSH) and catalase by 24% and 14.3%, respectively (p<0.05). In plasma an increase in MDA by 167.4% (p<0.01) and a decrease in oxidase activity of ceruloplasmin (CP) by 36.8% (p<0.001) were found. In the main group there was a decrease of accumulation of lipid peroxidation products in the blood. Intensity of detected changes depended on the antitumor effect: rats with growing LSP showed a tendency to the decrease in the RBC MDA level and normalization of plasma MDA; in animals with LSP regression this marker did not differ from normal values. In all animals of the main group the CP content was basically the same as in intact rats while GSH increased in the group without therapeutic effect (by 218.6%) and in the group with the effect by 69% (versus normal values; p<0.01). SOD activity in the rats with LSP growth significantly increased (by 42%), in the rats with regression decreased (by 30%) with subsequent normalization. Thus, administration of iron NPs caused activation of the antioxidant system in blood and a significant decrease in the manifestations of oxidative stress associated with tumor growth.

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential.

Multiple myeloma (MM) is a highly heterogeneous plasma cell malignancy. The MM cells reside in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, proliferation, and drug resistance. As in most cancers, the insulin-like growth factor (IGF) system has been demonstrated to play a key role in the pathogenesis of MM. The IGF system consists of IGF ligands, IGF receptors, IGF binding proteins (IGFBPs), and IGFBP proteases and contributes not only to the survival, proliferation, and homing of MM cells, but also MM-associated angiogenesis and osteolysis. Furthermore, increased IGF-I receptor (IGF-IR) expression on MM cells correlates with a poor prognosis in MM patients. Despite the prominent role of the IGF system in MM, strategies targeting the IGF-IR using blocking antibodies or small molecule inhibitors have failed to translate into the clinic. However, increasing preclinical evidence indicates that IGF-I is also involved in the development of drug resistance against current standard-of-care agents against MM, including proteasome inhibitors, immunomodulatory agents, and corticoids. IGF-IR targeting has been able to overcome or revert this drug resistance in animal models, enhancing the efficacy of standard-of-care agents. This finding has generated renewed interest in the therapeutic potential of IGF-I targeting in MM. The present review provides an update of the impact of the different IGF system components in MM and discusses the diagnostic and therapeutic potentials.

Macrophage Migration Inhibitory Factor Secretion Is Induced by Ionizing Radiation and Oxidative Stress in Cancer Cells.

The macrophage migration inhibitory factor (MIF) has been increasingly implicated in cancer development and progression by promoting inflammation, angiogenesis, tumor cell survival and immune suppression. MIF is overexpressed in a variety of solid tumor types in part due to its responsiveness to hypoxia inducible factor (HIF) driven transcriptional activation. MIF secretion, however, is a poorly understood process owing to the fact that MIF is a leaderless polypeptide that follows a non-classical secretory pathway. Better understanding of MIF processing and release could have therapeutic implications. Here, we have discovered that ionizing radiation (IR) and other DNA damaging stresses can induce robust MIF secretion in several cancer cell lines. MIF secretion by IR appears independent of ABCA1, a cholesterol efflux pump that has been implicated previously in MIF secretion. However, MIF secretion is robustly induced by oxidative stress. Importantly, MIF secretion can be observed both in cell culture models as well as in tumors in mice in vivo. Rapid depletion of MIF from tumor cells observed immunohistochemically is coincident with elevated circulating MIF detected in the blood sera of irradiated mice. Given the robust tumor promoting activities of MIF, our results suggest that an innate host response to genotoxic stress may mitigate the beneficial effects of cancer therapy, and that MIF inhibition may improve therapeutic responses.

Effects of CAR-regimen autohemochemotherapy on redox-dependent processes in erythrocytes of tumor-bearing organism in experimental ovarian cancer.

The purpose: The purpose of the study was to investigate the effect of the scheme autohemochemotherapy ATS on redox-dependent processes in red blood cells of tumor-bearing organism at an experimental ovarian cancer. Methods: We studied the dynamics of redox-dependent processes in red blood cells of rats with experimental ascitic ovarian tumor during CAP-regimen autohemochemotherapy (cyclophosphamide, doxorubicin and cisplatin). We assessed the indicators of oxidative modification of proteins in erythrocytes - carbonyl derivatives at l = 346 nm, 370 nm, 430 nm and 530 nm, the parameters of lipid peroxidation - malondialdehyde, ketodienes, diene conjugates, Schiff bases; the enzymatic part of antioxidant system - the activity of catalase, glutathione transferase and superoxide dismutase biochemically. Results: The red blood cells of tumor-bearing animals were found having increased the products of lipid peroxidation and oxidative modification of proteins while reducing the activity of antioxidant enzymes, suggesting a state of oxidative and carbonyl stress. Conclusion: We showed that extracorporeal incubation of cytotoxic drugs used in the CAP scheme with autoblood prior to infusion - the method of autohemochemotherapy - either in monochemotherapy, or in CAP-regimen, decreases the levels of lipid peroxidation, oxidative modification of proteins and increases activity of first line antioxidant defense enzymes - catalase and superoxide dismutase in circulating red blood cells. Such dynamics of redox-dependent processes suggests a stabilizing effect of autohemochemotherapy on circulating erythrocytes in a tumor-bearing organism.