Hypoxia is a non-physiological level of oxygen tension, a phenomenon common in a majority of malignant tumors. Tumor-hypoxia leads to advanced but dysfunctional vascularization and acquisition of epithelial-to-mesenchymal transition phenotype resulting in cell mobility and metastasis. Hypoxia alters cancer cell metabolism and contributes to therapy resistance by inducing cell quiescence. Hypoxia stimulates a complex cell signaling network in cancer cells, including the HIF, PI3K, MAPK, and NFĸB pathways, which interact with each other causing positive and negative feedback loops and enhancing or diminishing hypoxic effects. This review provides background knowledge on the role of tumor hypoxia and the role of the HIF cell signaling involved in tumor blood vessel formation, metastasis, and development of the resistance to therapy. Better understanding of the role of hypoxia in cancer progression will open new windows for the discovery of new therapeutics targeting hypoxic tumor cells and hypoxic microenvironment.

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The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation These EGFR aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways These pathways then activate many biological outputs that are beneficial to cancer cell proliferation, including their chronic initiation and progression through the cell cycle Here, we review the molecular mechanisms that regulate EGFR signal transduction, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression We focus on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways We also discuss the successes and challenges of EGFR-targeted therapies, and the potential for their use in combination with CDK4/6 inhibitors

Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways.

Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

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Regulation of immunity and inflammation by hypoxia in immunological niches

Our knowledge of pluripotent stem cell (PSC) biology has advanced to the point where we now can generate most cells of the human body in the laboratory. PSC-derived cardiomyocytes can be generated routinely with high yield and purity for disease research and drug development, and these cells are now gradually entering the clinical research phase for the testing of heart regeneration therapies. However, a major hurdle for their applications is the immature state of these cardiomyocytes. In this Review, we describe the structural and functional properties of cardiomyocytes and present the current approaches to mature PSC-derived cardiomyocytes. To date, the greatest success in maturation of PSC-derived cardiomyocytes has been with transplantation into the heart in animal models and the engineering of 3D heart tissues with electromechanical conditioning. In conventional 2D cell culture, biophysical stimuli such as mechanical loading, electrical stimulation and nanotopology cues all induce substantial maturation, particularly of the contractile cytoskeleton. Metabolism has emerged as a potent means to control maturation with unexpected effects on electrical and mechanical function. Different interventions induce distinct facets of maturation, suggesting that activating multiple signalling networks might lead to increased maturation. Despite considerable progress, we are still far from being able to generate PSC-derived cardiomyocytes with adult-like phenotypes in vitro. Future progress will come from identifying the developmental drivers of maturation and leveraging them to create more mature cardiomyocytes for research and regenerative medicine.

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Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine

The accumulation of knowledge associated with cancer biology continues to progress at a phenomenal rate; the electronic availability of research papers and news items makes access to new discoveries almost instantaneous. International meetings present opportunities to share scientific knowledge and develop collaborations, as well as fuelling competition between groups, to drive research forward. As a primary researcher or graduate student, the ability to adapt research projects to take advantage of new technological and scientific developments in the field of cancer biology requires a broad knowledge of subjects outside the primary areas of research. Similarly, an undergraduate or newcomer to the field must initially familiarise themselves with established principles before facing the daunting task of processing the vast amount of specialised knowledge available. The editors of The Molecular Biology of Cancer have identified the need for a book that assimilates critical aspects of cancer biology into a single resource to function as a reference tool and teaching aid applicable to both students and researchers alike.

The book is divided into 18 chapters and a glossary. Each chapter is authored by experts in the field and is prefaced by a list of the key points covered in that section. The chapters are organised according to a common format; of particular note is the arrangement of the bibliographies at the end of each chapter where references are grouped according to the concepts discussed. This format facilitates navigation of the information presented in each section, allowing the book to be used as a reference tool. This is ideal for established cancer biologists requiring clarity of specific subjects as well as those using the book to learn topics from first principles. It is in catering to this dual audience that the book is particularly strong.

The Introduction presents cancer as a genetic disease that requires the acquisition of the classical ‘hallmarks' by cancer cells to promote tumour development. Basic concepts are clearly presented in this chapter that would be redundant to an established cancer biologist but invaluable to a newcomer to the field and of great importance in the context of the book as a teaching resource. Chapter 2 considers the clinical features of lung, breast and prostate cancer and determines the context in which the molecular biology described in the subsequent chapters should be considered; namely, in terms of disease manifestation.

The interplay between the environment and genetic lesions associated with cancer is considered in Chapter 3; the book then focuses on the molecular basis of the cellular processes relevant to the cancer cell. The mechanisms fundamental to the normal cell cycle and DNA replication are described in Chapter 4; Chapters 6, 7 and 10 discuss the role of oncogenes, tumour suppressor genes and genetic instability, respectively. Chapter 11 describes the role of epigenetic factors in gene expression and the influence of post-translational modifications on protein expression. There is, however, comparatively little discussion of the role of signal transduction in cancer development. The vast nature of this field makes consideration of every pathway impossible in this context but a more thorough overview could be achieved if a whole chapter were devoted to this topic. The RAS – MAPK pathway and PI3K – Akt pathway are highlighted as examples of critical signalling modules in cell growth as part of Chapter 5 but could be included on their own. This is especially relevant given the potential of signalling pathway components as drug targets.

At times, the complex nature of the mechanisms and theories discussed necessitates detailed descriptions resulting in large blocks of text. However, large, monochrome figures clearly summarise these descriptions or are used in place of them where possible. Additional colour plates illustrate signalling pathways and clinical images that would be unclear in black and white. Information that is relevant to the chapter but would be incongruous in the main text, such as highlights of key experiments, is presented in additional text boxes. Tables are also used to present lists of information, such as protein classifications, in an organised format that would not be possible in the main text. The conclusion of each chapter summarises the topics covered and suggests questions that still remain in the field.

Chapters 15, 16 and 17 address the issues of cancer diagnosis, treatment and patient care and set the book apart from a general molecular biology reference by considering the clinical implications of understanding this subject. Chapter 17 is especially poignant in its highly informative discussion of the management of the palliative care of cancer patients. The title of the book does not imply that these topics would be included; however, it is information I feel is essential to complete the comprehensive reference guide that the editors aimed to produce. The development of therapies specifically targeting the molecules responsible for the transformed phenotype demands a detailed understanding of the mechanisms behind normal cellular processes. This knowledge should not be gained at the expense of an appreciation of the impact that bench-based research has on the patient in hospital. An awareness of the human implications of gaps in our understanding of cancer development should drive research.

The pace of cancer research means that the latest knowledge of highly specialised concepts is essential but, equally, the cross talk between different subject areas means a solid understanding is essential to take advantage of the plethora of new data available. Essentially, The Molecular Biology of Cancer is a book that can be used as an introduction to the subject as well as a platform on which to assimilate new information in the context of established principles. This book is applicable to both graduate and undergraduate students and, in the context of a research laboratory, this book would be an excellent resource as a reference guide for scientists at all levels.

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The Molecular Biology of Cancer

Cancer cells have been shown to have altered metabolism when compared to normal non-malignant cells. The Warburg effect describes a phenomenon in which cancer cells preferentially metabolize glucose by glycolysis, producing lactate as an end product, despite being the presence of oxygen. The phenomenon was first described by Otto Warburg in the 1920s, and has resurfaced as a controversial theory, with both supportive and opposing arguments. The biochemical aspects of the Warburg effect outline a strong explanation for the cause of cancer cell proliferation, by providing the biological requirements for a cell to grow. Studies have shown that pathways such as phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) as well as hypoxia inducible factor-1 (HIF-1) are central regulators of glycolysis, cancer metabolism and cancer cell proliferation. Studies have shown that PI3K signaling pathways have a role in many cellular processes such as metabolism, inflammation, cell survival, motility and cancer progression. Herein, the cellular aspects of the PI3K pathway are described, as well as the influence HIF has on cancer cell metabolism. HIF-1 activation has been related to angiogenesis, erythropoiesis and modulation of key enzymes involved in aerobic glycolysis, thereby modulating key processes required for the Warburg effect. In this review we discuss the molecular aspects of the Warburg effect with a particular emphasis on the role of the HIF-1 and the PI3K pathway.

Rupert Courtnay

Papers

Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K