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BBA - Reviews on Cancer (v.1835, #2)

Editorial Board (pp. i).

Circulating tumour cells and cancer stem cells: A role for proteomics in defining the interrelationships between function, phenotype and differentiation with potential clinical applications by Roberto Scatena; Patrizia Bottoni; Bruno Giardina (pp. 129-143).

Research on the discovery and implementation of valid cancer biomarkers is one of the most challenging fields in oncology and oncoproteomics in particular. Moreover, it is generally accepted that an evaluation of cancer biomarkers from the blood could significantly enable biomarker assessments by providing a relatively non-invasive source of representative tumour material. In this regard, circulating tumour cells (CTCs) isolated from the blood of metastatic cancer patients have significant promise. It has been demonstrated that localised and metastatic cancers may give rise to CTCs, which are detectable in the bloodstream. Despite technical difficulties, recent studies have highlighted the prognostic significance of the presence and number of CTCs in the blood. Future studies are necessary not only to detect CTCs but also to characterise them. Furthermore, another pathogenically significant type of cancer cells, known as cancer stem cells (CSCs) or more recently termed circulating tumour stem cells (CTSCs), appears to have a significant role as a subpopulation of CTCs.This review discusses the potential application of proteomic methodologies to improve the isolation and characterisation of CTCs and to distinguish between CTCs with a poor clinical significance and those with important biological and clinical implications.

Keywords: Cancer stem cells; Circulating tumour cells; Circulating tumour stem cells; Migrating cancer stem cells; Oncoproteomics; tumour markers

Dual character of Toll-like receptor signaling: Pro-tumorigenic effects and anti-tumor functions by Li Yu; Liantang Wang; Shangwu Chen (pp. 144-154).

As a major class of pattern-recognition receptors, Toll-like receptors (TLRs) play a critical role in defense against invading pathogens. Increasing evidence demonstrates that, in addition to infection, TLRs are involved in other important pathological processes, such as tumorigenesis. Activation of TLRs results in opposing outcomes, pro-tumorigenic effects and anti-tumor functions. TLR signaling can inhibit apoptosis and promote chronic inflammation-induced tumorigenesis. TLR activation in tumor cells and immune cells can induce production of cytokines, increase tumor cell proliferation and apoptosis resistance, promote invasion and metastasis, and inhibit immune cell activity resulting in tumor immune escape. In contrast, the engagement of other TLRs directly induces growth inhibition and apoptosis of tumor cells and triggers activation of immune cells enhancing anti-tumor immune responses. Thus, the interpretation of the precise function of each TLR in tumors is very important for targeting TLRs and using TLR agonists in tumor therapy. We review the role of TLR signaling in tumors and discuss the factors that affect outcomes of TLR activation.

Keywords: Abbreviations; AOM; Azoxymethane; BaP; Polycyclic aromatic hydrocarbons benzo[a]pyrene; BMDCs; Bone marrow-derived dendritic cells; CAC; Colitis-associated colorectal cancer; CCL5; Chemokine ligand 5; Cox-2; Cyclooxygenase-2; CpG-ODNs; CpG oligodeoxynucleotides; CYP1A1; Cytochrome P450 subclass 1A1; DC; Dendritic cell; DEN; Diethylnitrosamine; DSS; Dextran sodium sulfate; EGFR; Epidermal growth factor receptor; HCC; Hepatocellular carcinomas; HMGB1; High mobility group box-1 protein; HNSCC; Head and neck squamous cell carcinoma; HSPs; Heat shock proteins; IRF; IFN regulatory factor; IFNAR1; IFNα receptor 1; LLC; Lewis lung cancer; LPS; Lipopolysaccharide; MDA5; Melanoma differentiation-associated protein-5; mDCs; Myeloid dendritic cells; MM; Multiple myeloma; MyD88; Myeloid differentiation factor 88; NB; Neuroblastoma; PAMPs; Pathogen-associated molecular patterns; PBMC; Peripheral blood mononuclear cells; PGE; ₂; Prostaglandin E; ₂; PI3K; Phosphatidylinositol-3′-kinase; Poly(A:U); Polyadenylic-polyuridylic acid; Poly(I:C); Polyinosinic-polycytidylic acid; PRRs; Pattern-recognition receptors; PSK; Polysaccharide krestin; IRAK; Interleukin-1 receptor-associated kinase; SAA; Serum amyloid A; TAMs; Tumor associated macrophages; TIRAP; TIR domain-containing protein; TLRs; Toll-like receptors; TRAM; TRIF-related adaptor molecule; Treg; Regulatory T cells; TRIF; TIR domain-containing adaptor inducing interferon-β; WT; Wild typeToll-like receptor; Tumorigenesis; Pro-tumorigenic effects; Anti-tumor immunity

Genome-wide distribution of DNA methylation and DNA demethylation and related chromatin regulators in cancer by Yiqun Jiang; Shuang Liu; Xiang Chen; Ya Cao; Yongguang Tao (pp. 155-163).

DNA methylation plays an important role in the regulation of gene expression, as it is the first epigenetic modification to take place on a given DNA strand. Several factors may directly or indirectly regulate the dynamic distribution of DNA methylation and demethylation between intergenic and intragenic gene regions, thereby controlling gene expression. CpG islands have direct implications for the understanding of DNA methylation patterns in normal conditions and in some common disease states, including cancer. Here, we summarize several recent studies on the genome-wide distribution of DNA methylation and demethylation and their related factors, and we discuss the potential of DNA methylation and demethylation patterns to contribute to gene transcription patterns in tumorigenesis.

Keywords: DNA methylation; DNA demethylation; 5mC; 5hmC; DNMT; TET

Expression of glucose transporters in cancers by Leszek Szablewski (pp. 164-169).

It has been known for 80years that cancer cell growth in an energy-related process supported by an increased glucose metabolism. This phenomenon suggests a need for a corresponding increased uptake of glucose across the plasma membrane through an enhancement in the glucose transporter proteins, SGLT proteins as well as GLUT proteins. The results of many studies have demonstrated that the expression of glucose transporters, especially GLUT1, is increased in a variety of malignancies. GLUT1 overexpression has been found to be associated with tumor progression. It was found that GLUT1 overexpression is associated with poor overall survival in various malignant tumors.

Keywords: SGLTs expression; GLUTs expression; Cancers

Recruitment of monocytes/macrophages in different tumor microenvironments by Heon-Woo Lee; Hyun-Jung Choi; Sang-Jun Ha; Kyung-Tae Lee; Young-Guen Kwon (pp. 170-179).

After emigration from the bone marrow into the peripheral blood, monocytes enter tissues and differentiate into macrophages. Monocytes/macrophages have many roles in immune regulation, angiogenesis, and tumor metastasis and invasion. In addition, studies have revealed that these cells are essential to tumor progression. Recently, an accumulation of evidence has indicated that macrophages in distinct regions of tumor masses have distinct origins. For instance, classical monocytes appear to be a major source of macrophages in tumor epithelial, perivascular, and hypoxic regions. In contrast, non-classical monocytes are an important source of macrophages in the tumor perivascular region. During the past century, it has been demonstrated that several chemoattractants can regulate the recruitment of monocytes/macrophages to tumor sites. Despite the importance of monocytes/macrophages in tumor progression, there had been, until recently, no efforts to summarize receptor–ligand pairs between tumor-derived chemokines and corresponding receptors in monocytes in different microenvironments. In this review, we present a cohesive view of the distinct expression patterns of chemokine receptors in two different monocyte subsets (classical and non-classical monocytes) and describe their roles in monocyte/macrophage recruitment into distinct tumor microenvironments. This review provides insight into the behavior of monocytes/macrophages in different tumor microenvironments.

Keywords: Monocytes; Macrophages; Tumor microenvironment; Receptor–ligand interaction; Trafficking

Altered Ca2⁺ signaling in cancer cells: Proto-oncogenes and tumor suppressors targeting IP₃ receptors by Haidar Akl; Geert Bultynck (pp. 180-193).

Proto-oncogenes and tumor suppressors critically control cell-fate decisions like cell survival, adaptation and death. These processes are regulated by Ca2⁺ signals arising from the endoplasmic reticulum, which at distinct sites is in close proximity to the mitochondria. These organelles are linked by different mechanisms, including Ca2⁺-transport mechanisms involving the inositol 1,4,5-trisphosphate receptor (IP₃R) and the voltage-dependent anion channel (VDAC). The amount of Ca2⁺ transfer from the endoplasmic reticulum to mitochondria determines the susceptibility of cells to apoptotic stimuli. Suppressing the transfer of Ca2⁺ from the endoplasmic reticulum to the mitochondria increases the apoptotic resistance of cells and may decrease the cellular responsiveness to apoptotic signaling in response to cellular damage or alterations. This can result in the survival, growth and proliferation of cells with oncogenic features. Clearly, proper maintenance of endoplasmic reticulum Ca2⁺ homeostasis and dynamics including its links with the mitochondrial network is essential to detect and eliminate altered cells with oncogenic features through the apoptotic pathway. Proto-oncogenes and tumor suppressors exploit the central role of Ca2⁺ signaling by targeting the IP₃R. There are an increasing number of reports showing that activation of proto-oncogenes or inactivation of tumor suppressors directly affects IP₃R function and endoplasmic reticulum Ca2⁺ homeostasis, thereby decreasing mitochondrial Ca2⁺ uptake and mitochondrial outer membrane permeabilization. In this review, we provide an overview of the current knowledge on the proto-oncogenes and tumor suppressors identified as IP₃R-regulatory proteins and how they affect endoplasmic reticulum Ca2⁺ homeostasis and dynamics.Different proto-oncogenes and tumor suppressors target the IP₃ receptor (IP₃R), thereby regulating Ca2⁺-signaling events from the endoplasmic reticulum (ER) that control different hallmarks of cancer cells, including proliferation, apoptosis, autophagy and cellular bio-energetics.Display Omitted

Keywords: Abbreviations; AMPK; AMP-dependent kinase; Bcl-2-2; B-cell lymphoma 2; Bcl-X; _L; B-cell lymphoma extra large; BI-1; Bax Inhibitor-1; CLL; chronic lymphocytic leukemia; DL-BCL; diffuse-large B-cell lymphoma; E2; 17β-estradiol; FoxO; Forkhead box O; GSL; glycosphingolipids; IP; ₃; inositol 1,4,5-trisphosphate; IP; ₃; R; IP; ₃; receptor; KRAP; K-ras-induced actin-interacting protein; Mcl-1; myeloid cell leukemia-1; MCU; mitochondrial Ca; 2; ⁺; uniporter; MICU1; mitochondrial Ca; 2; ⁺; uptake 1; NCS-1; neuronal Ca; 2; ⁺; sensor 1; PI3K; phosphatidyl inositol-3 kinase; PML; promyelocytic leukemia protein; PTEN; phosphatase and tensin homolog deleted on chromosome 10; UPR; unfolded protein response; VDAC; voltage-dependent anion channelIntracellular Ca; 2; ⁺; signaling; IP; ₃; receptors; Proto-oncogenes; Tumor suppressors

Targeting LKB1 signaling in cancer by S.E. Korsse; M.P. Peppelenbosch; W. van Veelen (pp. 194-210).

The serine/threonine kinase LKB1 is a master kinase involved in cellular responses such as energy metabolism, cell polarity and cell growth. LKB1 regulates these crucial cellular responses mainly via AMPK/mTOR signaling. Germ-line mutations in LKB1 are associated with the predisposition of the Peutz–Jeghers syndrome in which patients develop gastrointestinal hamartomas and have an enormously increased risk for developing gastrointestinal, breast and gynecological cancers. In addition, somatic inactivation of LKB1 has been associated with sporadic cancers such as lung cancer. The exact mechanisms of LKB1-mediated tumor suppression remain so far unidentified; however, the inability to activate AMPK and the resulting mTOR hyperactivation has been detected in PJS-associated lesions. Therefore, targeting LKB1 in cancer is now mainly focusing on the activation of AMPK and inactivation of mTOR. Preclinical in vitro and in vivo studies show encouraging results regarding these approaches, which have even progressed to the initiation of a few clinical trials. In this review, we describe the functions, regulation and downstream signaling of LKB1, and its role in hereditary and sporadic cancers. In addition, we provide an overview of several AMPK activators, mTOR inhibitors and additional mechanisms to target LKB1 signaling, and describe the effect of these compounds on cancer cells. Overall, we will explain the current strategies attempting to find a way of treating LKB1-associated cancer.

Keywords: LKB1; Peutz–Jeghers syndrome; Sporadic cancer; Rapamycin; Metformin; mTOR

Hsp90: Still a viable target in prostate cancer by Margaret M. Centenera; Alyssa K. Fitzpatrick; Wayne D. Tilley; Lisa M. Butler (pp. 211-218).

Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates the maturation, activation and stability of critical signaling proteins that drive the development and progression of prostate cancer, including the androgen receptor. Despite robust preclinical data demonstrating anti-tumor activity of first-generation Hsp90 inhibitors in prostate cancer, poor clinical responses initially cast doubt over the clinical utility of this class of agent. Recent advances in compound design and development, use of novel preclinical models and further biological insights into Hsp90 structure and function have now stimulated a resurgence in enthusiasm for these drugs as a therapeutic option. This review highlights how the development of new-generation Hsp90 inhibitors with improved physical and pharmacological properties is unfolding, and discusses the potential contexts for their use either as single agents or in combination, for men with metastatic prostate cancer.

Keywords: Hsp90; Inhibitors; Prostate cancer; Clinical trials

Cholesterol accumulation in prostate cancer: A classic observation from a modern perspective by James Robert Krycer; Andrew John Brown (pp. 219-229).

Prostate cancer (PCa) is the most common cancer in men in developed countries. Epidemiological studies have associated high blood-cholesterol levels with an increased risk of PCa, whilst cholesterol-lowering drugs (statins) reduce the risk of advanced PCa. Furthermore, normal prostate epithelial cells have an abnormally high cholesterol content, with cholesterol levels increasing further during progression to PCa. In this review, we explore why and how this occurs.Concurrent to this observation, intense efforts have been expended in cardiovascular research to better understand the regulators of cholesterol homeostasis. Here, we apply this knowledge to elucidate the molecular mechanisms driving the accumulation of cholesterol in PCa. For instance, recent evidence from our group and others shows that major signalling players in prostate growth and differentiation, such as androgens and Akt, modulate the key transcriptional regulators of cholesterol homeostasis to enhance cholesterol levels. This includes adjusting central carbon metabolism to sustain greater lipid synthesis. Perturbations in cholesterol homeostasis appear to be maintained even when PCa approaches the advanced, ‘castration-resistant’ state. Overall, this provides a link between cholesterol accumulation and PCa cell growth. Given there is currently no cure for castration-resistant PCa, could cholesterol metabolism be a novel target for PCa therapy?Overall, this review presents a picture that cholesterol metabolism is important for PCa development: growth-promoting factors stimulate cholesterol accumulation, which in turn presents a possible target for chemotherapy. Consequently, we recommend future investigations, both to better elucidate the mechanisms driving this accumulation and applying it in novel chemotherapeutic strategies.Display Omitted

Keywords: Abbreviations; ADT; androgen deprivation therapy; AR; androgen receptor; ABCA1/G1; ATP-binding cassette transporter isoform A1/G1; CR-PCa; castration-resistant PCa; BPH; benign prostatic hyperplasia; DHCR24; 3β-hydroxysterol Δ24-reductase; FASN; fatty acid synthase; HMGCR; HMG-CoA reductase; LDL; low-density lipoprotein; LDLR; LDL receptor; LXR; liver X receptor; PCa; prostate cancer; RXR; retinoid X receptor; SR-BI; scavenger receptor class B member I; SREBP; sterol regulatory element-binding proteinProstate cancer; Cholesterol; Androgen receptor; Sterol regulatory element-binding protein; Liver X receptor

Molecular mapping the presence of druggable targets in preinvasive and precursor breast lesions: A comprehensive review of biomarkers related to therapeutic interventions by David P. Boyle; Paul Mullan; Manuel Salto-Tellez (pp. 230-242).

The analysis of clinical breast samples using biomarkers is integral to current breast cancer management. Currently, a limited number of targeted therapies are standard of care in breast cancer treatment. However, these targeted therapies are only suitable for a subset of patients and resistance may occur. Strategies to prevent the occurrence of invasive lesions are required to reduce the morbidity and mortality associated with the development of cancer. In theory, application of targeted therapies to pre-invasive lesions will prevent their progression to invasive lesions with full malignant potential. The diagnostic challenge for pathologists is to make interpretative decisions on early detected pre-invasive lesions. Overall, only a small proportion of these pre-invasive lesions will progress to invasive carcinoma and morphological assessment is an imprecise and subjective means to differentiate histologically identical lesions with varying malignant potential. Therefore differential biomarker analysis in pre-invasive lesions may prevent overtreatment with surgery and provide a predictive indicator of response to therapy. There follows a review of established and emerging potential druggable targets in pre-invasive lesions and correlation with lesion morphology.

Keywords: Breast cancer; Pre-invasive; Biomarker; Druggable targets; Chemoprevention

Eph receptors and their ligands: Promising molecular biomarkers and therapeutic targets in prostate cancer by Jessica E. Lisle; Inga Mertens-Walker; Raphael Rutkowski; Adrian C. Herington; Sally-Anne Stephenson (pp. 243-257).

Although at present, there is a high incidence of prostate cancer, particularly in the Western world, mortality from this disease is declining and occurs primarily only from clinically significant late stage tumors with a poor prognosis. A major current focus of this field is the identification of new biomarkers which can detect earlier, and more effectively, clinically significant tumors from those deemed “low risk”, as well as predict the prognostic course of a particular cancer. This strategy can in turn offer novel avenues for targeted therapies. The large family of Receptor Tyrosine Kinases, the Ephs, and their binding partners, the ephrins, has been implicated in many cancers of epithelial origin through stimulation of oncogenic transformation, tumor angiogenesis, and promotion of increased cell survival, invasion and migration. They also show promise as both biomarkers of diagnostic and prognostic value and as targeted therapies in cancer. This review will briefly discuss the complex roles and biological mechanisms of action of these receptors and ligands and, with regard to prostate cancer, highlight their potential as biomarkers for both diagnosis and prognosis, their application as imaging agents, and current approaches to assessing them as therapeutic targets. This review demonstrates the need for future studies into those particular family members that will prove helpful in understanding the biology and potential as targets for treatment of prostate cancer.

Keywords: Eph receptors; Ephrin ligands; Prostate cancer; Biomarkers; Therapeutic targets; Exosomes

Corrigendum to “The role of CXC chemokines in the transition of chronic inflammation to esophageal and gastric cancer” [Biochim. Biophys. Acta 1825 (2012) 117–129] by Hannelien Verbeke; Karel Geboes; Jo Van Damme; Sofie Struyf (pp. 258-258).

Retraction notice to “Immunosuppressive networks in the tumour environment and their effect in dendritic cells” [Biochim. Biophys. Acta (1795) (2009) 16–24] by Karim Bennaceur; Jessica Alice Chapman; Jean-Louis Touraine; Jacques Portoukalian (pp. 259-259).

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BBA - Reviews on Cancer (v.1835, #2)