BBA - Reviews on Cancer (v.1855, #2)

Tumor-associated macrophages are a critical component of tumor microenvironments, which affect tumor growth, tumor angiogenesis, immune suppression, metastasis and chemoresistance. There is emerging evidence that many anticancer modalities currently used in the clinic have unique and distinct properties that modulate the recruitment, polarization and tumorigenic activities of macrophages in the tumor microenvironments. Educated tumor-associated macrophages significantly impact the clinical efficacies of and resistance to these anticancer modalities. Moreover, the development of drugs targeting tumor-associated macrophages, especially c-Fms kinase inhibitors and humanized antibodies targeting colony-stimulating factor-1 receptor, are in early clinical stages and show promising benefit for cancer patients. These experimental and clinical findings prompted us to further evaluate the potential targets that exhibit tumorigenic and immunosuppressive potential in a manner specific for tumor associated macrophages.
Keywords: Tumor-associated macrophages; Tumor microenvironments; Anti-cancer therapy; CSF-1 receptor inhibitor;

Runx3 at the interface of immunity, inflammation and cancer by Joseph Lotem; Ditsa Levanon; Varda Negreanu; Omri Bauer; Shay Hantisteanu; Joseph Dicken; Yoram Groner (131-143).
Inactivation of tumor suppressor genes (TSG) in normal cells provides a viability/growth advantage that contributes cell-autonomously to cancer. More than a decade ago claims arose that the RUNX3 member of the RUNX transcription factor family is a major TSG inactivated in gastric cancer, a postulate extended later to other cancers. However, evidence that Runx3 is not expressed in normal gastric and other epithelia has challenged the RUNX3-TSG paradigm. Here we critically re-appraise this paradigm in light of recent high-throughput, quantitative genome-wide studies on thousands of human samples of various tumors and new investigations of the role of Runx3 in mouse cancer models. Collectively, these studies unequivocally demonstrate that RUNX3 is not a bona fide cell-autonomous TSG. Accordingly, RUNX3 is not recognized as a TSG and is not included among the 2000 cancer genes listed in the “Cancer Gene Census” or “Network for Cancer Genes” repositories. In contrast, RUNX3 does play important functions in immunity and inflammation and may thereby indirectly influence epithelial tumor development.
Keywords: RUNX3; Cancer; Tumor suppressor gene; DNA methylation; Immunity; Inflammation;

5-Hydroxymethylcytosine: An epigenetic mark frequently deregulated in cancer by Leonie I. Kroeze; Bert A. van der Reijden; Joop H. Jansen (144-154).
The epigenetic mark 5-hydroxymethylcytosine (5hmC) has gained interest since 2009, when it was discovered that Ten-Eleven-Translocation (TET) proteins catalyze the conversion of 5-methylcytosine (5mC) into 5hmC. This conversion appears to be an intermediate step in the active DNA demethylation pathway. Factors that regulate DNA hydroxymethylation are frequently affected in cancer, leading to deregulated 5hmC levels. In this review, we will discuss the regulation of DNA hydroxymethylation, defects in this pathway in cancer, and novel therapies that may correct deregulated (hydroxy)methylation of DNA.
Keywords: 5-Hydroxymethylcytosine; DNA methylation; Cancer; TET; IDH;

Vaccination approach to anti-angiogenic treatment of cancer by Madelon Q. Wentink; Elisabeth J.M. Huijbers; Tanja D. de Gruijl; Henk M.W. Verheul; Anna-Karin Olsson; Arjan W. Griffioen (155-171).
Improvement of patient survival by anti-angiogenic therapy has proven limited. A vaccination approach inducing an immune response against the tumor vasculature combines the benefits of immunotherapy and anti-angiogenesis, and may overcome the limitations of current anti-angiogenic drugs. Strategies to use whole endothelial cell vaccines and DNA- or protein vaccines against key players in the VEGF signaling axis, as well as specific markers of tumor endothelial cells, have been tested in preclinical studies. Current clinical trials are now testing the promise of this specific anti-cancer vaccination approach. This review will highlight the state-of-the-art in this exciting field of cancer research.
Keywords: Angiogenesis; Immunology; Tumor vasculature; Vaccination;

Role of tumor hypoxia in acquisition of resistance to microtubule-stabilizing drugs by Viswanath Das; Jana Štěpánková; Marián Hajdúch; John H. Miller (172-182).
Microtubules, an important cytoskeletal protein involved in mitotic and non-mitotic functions of cells, are important targets in cancer therapy. Microtubule-stabilizing drugs like the taxanes are critical adjuvant and palliative first-line therapies for the treatment of early, advanced and metastatic solid tumors of different lineages. Their adverse on- and off-target effects and high susceptibility to multidrug resistance, however, are major challenges encountered in the clinic in the treatment of solid cancers. Although biochemical resistance to microtubule-stabilizing drugs has been well characterized, molecular mechanisms that contribute to clinical resistance to taxanes in solid tumors still remain poorly understood and uncontrolled. The heterogeneous tumor microenvironment leads to greater diversity of resistance mechanisms to taxanes. Tumor hypoxia, a prominent feature of solid tumors, results in a broad range of effects on a number of cellular pathways and is one of the major contributors to the development of resistance to not only microtubule-stabilizing drugs but also other anticancer drugs. In this review, we highlight the potential role of hypoxia in the development of resistance to taxanes through mechanisms that involve altering the cell cycle, changing the properties of microtubules, and inducing the overexpression of gene products that contribute to drug resistance. Hypoxia-induced challenges described in this review are not limited to microtubule-stabilizing drugs alone, but in many cases also impact on treatment with non-microtubule-targeting anticancer drugs.Display Omitted
Keywords: Cancer; Hypoxia; Microtubules; Resistance; Paclitaxel;

Transcription factors and chromatin proteins as therapeutic targets in cancer by Simon J. Johnston; Jason S. Carroll (183-192).
Targeting the factors that regulate gene transcription is a compelling strategy in cancer therapeutics. Traditionally, these have been considered intractable targets, but recent work has revealed novel strategies for the regulation of transcription factor activity in cancer. This review will highlight some of the emerging concepts and provide examples where agents that target transcription factors are being exploited clinically for cancer therapies.
Keywords: Transcription factors; Cancer; Drugs; Small molecules; siRNA; Nuclear receptors;

Sustained angiogenesis is a hallmark of cancer. Because of the primary role of vascular endothelial growth factors (VEGFs) and their receptors in angiogenesis, VEGF-targeted agents have been developed to inhibit these signaling processes in non-small cell lung cancer (NSCLC). However, the clinical benefits are transient and resistance often rapidly develops. Insights into the molecular mechanisms of resistance would help to develop novel strategies to improve the efficacy of antiangiogenic therapies. This review discusses the mechanisms of resistance to anti-VEGF therapy and the postulated strategies to optimize antiangiogenic therapy. A number of multitargeted tyrosine kinase inhibitors currently in phase III clinical development for NSCLC are summarized. The emerging combination of antiangiogenic therapy with tumor immunotherapy is also discussed.
Keywords: Angiogenesis; Multitargeted kinase inhibitor; Vascular endothelial growth factor; NSCLC;

For this comprehensive review, 257 publications with the keywords “osteopontin” or “OPN” and “vascular endothelial growth factor” or “VEGF” in PubMed were screened (time frame from year 1996 to year 2014). 37 articles were excluded because they were not focused on the interactions between these molecules, and papers relevant for transformation-related phenomena were selected. Osteopontin (OPN) and vascular endothelial growth factor (VEGF) are characterized by a convergence in function for regulating cell motility and angiogenesis, the response to hypoxia, and apoptosis. Often, they are co-expressed or one molecule induces the other, however, in some settings OPN-associated pathways and VEGF-associated pathways are distinct. Their relationships affect the pathogenesis in cancer, where they contribute to progression and angiogenesis and serve as markers for poor prognosis. The inhibition of OPN may reduce VEGF levels and suppress tumor progression. In vascular pathologies, these two cytokines mediate remodeling, but may also perpetuate inflammation and narrowing of the arteries. OPN and VEGF are elevated and contribute to vascularization in inflammatory diseases.
Keywords: Angiogenesis; Hypoxia; Apoptosis; Cancer; Vascular disease; Immune system;

Prioritizing therapeutic targets using patient-derived xenograft models by K.A. Lodhia; A.M. Hadley; P. Haluska; C.L. Scott (223-234).
Effective systemic treatment of cancer relies on the delivery of agents with optimal therapeutic potential. The molecular age of medicine has provided genomic tools that can identify a large number of potential therapeutic targets in individual patients, heralding the promise of personalized treatment. However, determining which potential targets actually drive tumor growth and should be prioritized for therapy is challenging. Indeed, reliable molecular matches of target and therapeutic agent have been stringently validated in the clinic for only a small number of targets. Patient-derived xenografts (PDXs) are tumor models developed in immunocompromised mice using tumor procured directly from the patient. As patient surrogates, PDX models represent a powerful tool for addressing individualized therapy. Challenges include humanizing the immune system of PDX models and ensuring high quality molecular annotation, in order to maximize insights for the clinic. Importantly, PDX can be sampled repeatedly and in parallel, to reveal clonal evolution, which may predict mechanisms of drug resistance and inform therapeutic strategy design.
Keywords: Personalized medicine; Patient-derived xenografts; Genomics; Targeted therapy; Therapeutic targets;

Galectin expression in cancer diagnosis and prognosis: A systematic review by Victor L. Thijssen; Roy Heusschen; Jo Caers; Arjan W. Griffioen (235-247).
Galectins are a family of proteins that bind to specific glycans thereby deciphering the information captured within the glycome. In the last two decades, several galectin family members have emerged as versatile modulators of tumor progression. This has initiated the development and preclinical assessment of galectin-targeting compounds. With the first compounds now entering clinical trials it is pivotal to gain insight in the diagnostic and prognostic value of galectins in cancer as this will allow a more rational selection of the patients that might benefit most from galectin-targeted therapies. Here, we present a systematic review of galectin expression in human cancer patients. Malignant transformation is frequently associated with altered galectin expression, most notably of galectin-1 and galectin-3. In most cancers, increased galectin-1 expression is associated with poor prognosis while elevated galectin-9 expression is emerging as a marker of favorable disease outcome. The prognostic value of galectin-3 appears to be tumor type dependent and the other galectins require further investigation. Regarding the latter, additional studies using larger patient cohorts are essential to fully unravel the diagnostic and prognostic value of galectin expression. Furthermore, to better compare different findings, consensus should be reached on how to assess galectin expression, not only with regard to localization within the tissue and within cellular compartments but also regarding alternative splicing and genomic variations. Finally, linking galectin expression and function to aberrant glycosylation in cancer cells will improve our understanding of how these versatile proteins can be exploited for diagnostic, prognostic and even therapeutic purposes in cancer patients.Display Omitted
Keywords: Glycobiology; Tumor; Patients; Overall survival; Therapy; Clinical trials;

Fighting the force: Potential of homeobox genes for tumor microenvironment regulation by Josette M. Northcott; Jason J. Northey; J. Matthew Barnes; Valerie M. Weaver (248-253).
Tumor cells exist in a constantly evolving stromal microenvironment composed of vasculature, immune cells and cancer-associated fibroblasts, all residing within a dynamic extracellular matrix. In this review, we examine the biochemical and biophysical interactions between these various stromal cells and their matrix microenvironment. While the stroma can alter tumor progression via multiple mechanisms, we emphasize the role of homeobox genes in detecting and modulating the mechanical changes in the microenvironment during tumor progression.
Keywords: Tumor microenvironment; Extracellular matrix; Stiffness; Stromal cells; Homeobox genes;

Chemopreventive effects of aspirin at a glance by Muhammad Waqas Usman; Fuwen Luo; Hailing Cheng; Jean J. Zhao; Pixu Liu (254-263).
Experimental, epidemiological, and clinical data from the last two decades have each supported the hypothesis that aspirin possesses anticancer properties, and that its use may also reduce the lifetime probability of developing or dying from a number of cancers. Aspirin's ability to act on multiple key metabolic and signaling pathways via inhibition of the cyclooxygenase (COX) enzyme, as well as through COX-independent mechanisms, makes it particularly relevant in the fight against cancer. A growing body of evidence indicates that aspirin may not only reduce cancer risk, but also prevent metastasis and angiogenesis while slowing the rate of mutation-inducing DNA damage. These emerging benefits of aspirin are offset to some extent by the known risks of treatment, such as cardiovascular events and gastrointestinal bleeding. However, it has been shown that pre-treatment risk assessment of individual patients and the use of proton pump inhibitors or Helicobacter pylori eradication therapy concomitantly with aspirin treatment can reduce these potential risks. Thus, the significant benefits of aspirin treatment, coupled with recent data concerning its risks, may prove to tip the balance in favor of aspirin use in cancer prevention.
Keywords: Aspirin; Cancer; Chemoprevention; Cyclooxygenase;

Inferring mutational timing and reconstructing tumour evolutionary histories by Samra Turajlic; Nicholas McGranahan; Charles Swanton (264-275).
Cancer evolution can be considered within a Darwinian framework. Both micro and macro-evolutionary theories can be applied to understand tumour progression and treatment failure. Owing to cancers' complexity and heterogeneity the rules of tumour evolution, such as the role of selection, remain incompletely understood. The timing of mutational events during tumour evolution presents diagnostic, prognostic and therapeutic opportunities. Here we review the current sampling and computational approaches for inferring mutational timing and the evidence from next generation sequencing-informed data on mutational timing across all tumour types. We discuss how this knowledge can be used to illuminate the genes and pathways that drive cancer initiation and relapse; and to support drug development and clinical trial design.
Keywords: Mutational timing; Intratumour heterogeneity; Cancer evolution; Subclonal mutations; Treatment resistance;

Insights into the key roles of proteoglycans in breast cancer biology and translational medicine by Achilleas D. Theocharis; Spyros S. Skandalis; Thomas Neill; Hinke A.B. Multhaupt; Mario Hubo; Helena Frey; Sandeep Gopal; Angélica Gomes; Nikos Afratis; Hooi Ching Lim; John R. Couchman; Jorge Filmus; Ralph D. Sanderson; Liliana Schaefer; Renato V. Iozzo; Nikos K. Karamanos (276-300).
Proteoglycans control numerous normal and pathological processes, among which are morphogenesis, tissue repair, inflammation, vascularization and cancer metastasis. During tumor development and growth, proteoglycan expression is markedly modified in the tumor microenvironment. Altered expression of proteoglycans on tumor and stromal cell membranes affects cancer cell signaling, growth and survival, cell adhesion, migration and angiogenesis. Despite the high complexity and heterogeneity of breast cancer, the rapid evolution in our knowledge that proteoglycans are among the key players in the breast tumor microenvironment suggests their potential as pharmacological targets in this type of cancer. It has been recently suggested that pharmacological treatment may target proteoglycan metabolism, their utilization as targets for immunotherapy or their direct use as therapeutic agents. The diversity inherent in the proteoglycans that will be presented herein provides the potential for multiple layers of regulation of breast tumor behavior. This review summarizes recent developments concerning the biology of selected proteoglycans in breast cancer, and presents potential targeted therapeutic approaches based on their novel key roles in breast cancer.
Keywords: Proteoglycans; Decorin; Syndecans; Glypicans; Serglycin; Breast cancer;

Corrigendum to “Membrane rafts as a novel target in cancer therapy” [BBACAN 1845(2) (2014) 155–165] by Anita Hryniewicz-Jankowska; Katarzyna Augoff; Agnieszka Biernatowska; Joanna Podkalicka; Aleksander F. Sikorski (301).