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Constitutive NF ?B signaling promotes survival in multiple myeloma (MM) and other cancers; however current NF ?B targeting strategies lack cancer cell specificity. Here we identify the interaction between the NF ?B regulated antiapoptotic factor GADD45ß and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug discovery strategy we developed DTP3 a D tripeptide which disrupts the GADD45ß/MKK7 complex kills MM cells effectively and importantly lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard bortezomib but more than 100 fold higher cancer cell specificity in vitro. Notably DTP3 ablates myeloma xenografts in mice with no apparent side effects at the effective doses. Hence cancer selective targeting of the NF ?B pathway is possible and at least for myeloma patients promises a profound benefit.

Inflammatory infiltrate. Lymphocytes (green arrows), plasma cells (yellow arrows), macrophages (red arrows), and PMN (blue arrow). (PPTX 1448Â kb)

MiRNAs differentially modulated during the progression of the hepatic damage. (A) RQ (relative quantification) values ± SE (Y axis) obtained by comparing HF to LF pooled RNAs from hepatic tissues. (B) RQ values ± SE (Y axis) of pooled RNAs from tumor tissues with respect to pooled RNAs from HF hepatic non-tumor tissues. Results are from 3 replicates. Global normalization mode was used for the analysis. Samples marked with the asterisk show P ≤ 0.05. (PDF 284 kb)

Inflammatory infiltrate. Lymphocytes (green arrows), plasma cells (yellow arrows), macrophages (red arrows), and PMN (blue arrow). (PPTX 1448Â kb)

MiRNAs differentially modulated during the progression of the hepatic damage. (A) RQ (relative quantification) values ± SE (Y axis) obtained by comparing HF to LF pooled RNAs from hepatic tissues. (B) RQ values ± SE (Y axis) of pooled RNAs from tumor tissues with respect to pooled RNAs from HF hepatic non-tumor tissues. Results are from 3 replicates. Global normalization mode was used for the analysis. Samples marked with the asterisk show P ≤ 0.05. (PDF 284 kb)

Cancer is a multistep process characterized by various and different genetic lesions which cause the transformation of normal cells into tumor cells. To preserve the genomic integrity, eukaryotic cells need a complex DNA damage/repair response network of signaling pathways, involving many proteins, able to induce cell cycle arrest, apoptosis, or DNA repair. Chemotherapy and/or radiation therapy are the most commonly used therapeutic approaches to manage cancer and act mainly through the induction of DNA damage. Impairment in the DNA repair proteins, which physiologically protect cells from persistent DNA injury, can affect the efficacy of cancer therapies. Recently, increasing evidence has suggested that microRNAs take actively part in the regulation of the DNA damage/repair network. MicroRNAs are endogenous short noncoding molecules able to regulate gene expression at the post-transcriptional level. Due to their activity, microRNAs play a role in many fundamental physiological and pathological processes. In this review we report and discuss the role of microRNAs in the DNA damage/repair and cancer.

Constitutive NF-B-K signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-B-K-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-B-K-regulated antiapoptotic factor GADD45 beta and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45 beta/ MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard, bortezomib, but more than 100-fold higher cancer cell specificity in vitro. Notably, DTP3 ablates rnyeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-KB pathway is possible and, at least for myeloma patients, promises a profound benefit.

Cancer affects millions of people worldwide. Tumor mortality is substantially due to diagnosis at stages that are too late for therapies to be effective. Advances in screening methods have improved the early diagnosis, prognosis, and survival for some cancers. Several validated biomarkers are currently used to diagnose and monitor the progression of cancer, but none of them shows adequate specificity, sensitivity, and predictive value for population screening. So, there is an urgent need to isolate novel sensitive, specific biomarkers to detect the disease early and improve prognosis, especially in high-mortality tumors. Proteomic techniques are powerful tools to help in diagnosis and monitoring of treatment and progression of the disease. During the last decade, mass spectrometry has assumed a key role in most of the proteomic analyses that are focused on identifying cancer biomarkers in human serum, making it possible to identify and characterize at the molecular level many proteins or peptides differentially expressed. In this paper we summarize the results of mass spectrometry serum profiling and biomarker identification in high mortality tumors, such as ovarian, liver, lung, and pancreatic cancer.

Hepatocellular carcinoma (HCC) is one of the most common and aggressive human cancers worldwide. HCC is an example of inflammation-related cancer and represents a paradigm of the relation occurring between tumor microenvironment and tumor development. Tumor-associated macrophages (TAMs) are a major component of leukocyte infiltrate of tumors and play a pivotal role in tumor progression of inflammation-related cancer, including HCC. Several studies indicate that, in the tumor microenvironment, TAMs acquire an M2-polarized phenotype and promote angiogenesis, metastasis, and suppression of adaptive immunity through the expression of cytokines, chemokines, growth factors, and matrix metalloproteases. Indeed, an established M2 macrophage population has been associated with poor prognosis in HCC. The molecular links that connect cancer cells and TAMs are not completely known, but recent studies have demonstrated that NF-κB, STAT-3, and HIF-1 signaling pathways play key roles in this crosstalk. In this paper, we discuss the current knowledge about the role of TAMs in HCC development, highlighting the role of TAM-derived cytokines, chemokines, and growth factors in the initiation and progression of liver cancer and outlining the signaling pathways involved in the interplay between cancer cells and TAMs.

The full activation of T cells necessitates the concomitant activation of two signals, the engagement of T-cell receptor by peptide/major histocompatibility complex II and an additional signal delivered by costimulatory molecules. The best characterized costimulatory molecules belong to B7/CD28 and TNF/TNFR families and play crucial roles in the modulation of immune response and improvement of antitumor immunity. Unfortunately, tumors often generate an immunosuppressive microenvironment, where T-cell response is attenuated by the lack of costimulatory molecules on the surface of cancer cells. Thus, targeting costimulatory pathways represent an attractive therapeutic strategy to enhance the antitumor immunity in several human cancers. Here, latest therapeutic approaches targeting costimulatory molecules will be described.