Molecular biology for the radiation oncologist: the 5Rs of radiobiology meet the hallmarks of cancer

Recent advances in our understanding of the biology of cancer have provided enormous opportunities for the development of novel therapies against specific molecular targets. It is likely that most of these targeted therapies will have only modest single agent activities but may have the potential to accentuate the therapeutic effects of ionising radiation. In this introductory review, the 5Rs of classical radiobiology are interpreted in terms of their relationship to the hallmarks of cancer. Future articles will focus on the specific hallmarks of cancer and will highlight the opportunities that exist for designing new combination treatment regimens.     

Development of anticancer drugs based on the hallmarks of tumor cells

Cancer remains a public health problem with a high unmet medical demand. However, in recent decades, the knowledge of several functional molecular and biological traits that distinguish tumor cells from normal cells, known as the hallmarks of cancer as described by Hannahan and Weinberg, has led to new and modern therapeutic approaches against this disease. Most cancer drugs are deliberately developed for specific molecular targets that involve these hallmarks. In this review, we address the currently available cancer drugs and development of new drugs from the perspective of their interaction with these hallmarks as well as the pathways and mechanisms involved.     

Exploiting the hallmarks of cancer: the future conquest of breast cancer

What separates a malignant from a normal cell? This question has occupied scientists for decades. Although a simple answer remains elusive, several hallmarks of malignancy have been identified. These critical features include uncontrolled proliferation, insensitivity to negative growth regulation, evasion of apoptosis, lack of senescence, invasion and metastasis, angiogenesis and genomic elasticity. Existing therapies predominantly target proliferation either with cytotoxic agents, ionising radiation or more targeted attacks on growth factor signalling pathways. Our most successful therapies to date inhibit proliferation via the oestrogen receptor (ER) and HER2 pathways. Further improvements in therapy must attack the other hallmarks of malignancy and will undoubtedly be accompanied by a better means of individual patient selection for such therapies. Indeed, each of these hallmarks presents a therapeutic opportunity. To believe otherwise would be to assume that a feature is both biologically crucial, yet therapeutically unimportant, an unlikely paradox. Here, we suggest the hallmarks of malignancy as a conceptual framework for understanding novel breast cancer therapies.     

Killing a cancer: what are the alternatives?

Evading programmed cell death is one of the hallmarks of cancer. Conversely, inducing cell death by pharmacological means is the basis of almost every non-invasive cancer therapy. Research over the past decade has greatly increased our understanding of non-apoptotic programmed cell death events, such as lysosomal-mediated cell death, necroptosis and cell death with autophagy. It is becoming clear that an intricate effector network connects many of these classical and non-classical death pathways. In this Review, we discuss converging and diverging features of these pathways, as well as attempts to exploit this newly gained knowledge pharmacologically to provide therapeutics for cancer.     

Evolutionary mechanism unifies the hallmarks of cancer

The basis for the gene mutation theory of cancer that dominates current molecular cancer research consists of: the belief that gene‐level aberrations such as mutations are the main cause of cancers, the concept that stepwise gene mutation accumulation drives cancer progression, and the hallmarks of cancer. The research community swiftly embraced the hallmarks of cancer, as such synthesis has supported the notions that common cancer genes are responsible for the majority of cancers and the complexity of cancer can be dissected into simplified molecular principles. The gene/pathway classification based on individual hallmarks provides explanation for the large number of diverse gene mutations, which is in contrast to the original estimation that only a handful of gene mutations would be discovered. Further, these hallmarks have been highly influential as they also provide the rationale and research direction for continued gene‐based cancer research. While the molecular knowledge of these hallmarks is drastically increasing, the clinical implication remains limited, as cancer dynamics cannot be summarized by a few isolated/fixed molecular principles. Furthermore, the highly heterogeneous genetic signature of cancers, including massive stochastic genome alterations, challenges the utility of continuously studying each individual gene mutation under the framework of these hallmarks. It is therefore necessary to re‐evaluate the concept of cancer hallmarks through the lens of cancer evolution. In this analysis, the evolutionary basis for the hallmarks of cancer will be discussed and the evolutionary mechanism of cancer suggested by the genome theory will be employed to unify the diverse molecular mechanisms of cancer.     

DNA replication stress and cancer chemotherapy

DNA replication is one of the fundamental biological processes in which dysregulation can cause genome instability. This instability is one of the hallmarks of cancer and confers genetic diversity during tumorigenesis. Numerous experimental and clinical studies have indicated that most tumors have experienced and overcome the stresses caused by the perturbation of DNA replication, which is also referred to as DNA replication stress (DRS). When we consider therapeutic approaches for tumors, it is important to exploit the differences in DRS between tumor and normal cells. In this review, we introduce the current understanding of DRS in tumors and discuss the underlying mechanism of cancer therapy from the aspect of DRS.     

肿瘤新特征研究进展

2011年HANAHAN和WEINBERG提出肿瘤具有十大标志性特征,过去10年我们对肿瘤的特征又有了新认识,这些新的肿瘤特征包括表观遗传可塑、细胞自食、克隆进化、肿瘤内异质性、共生微生物群失调和生物钟紊乱。靶向肿瘤新特征产生了肿瘤表观遗传治疗、进化治疗、精准治疗、微生物治疗和时间治疗等新治疗模式。联合治疗和精准治疗将是未来肿瘤治疗的方向。     

Progress and assessment of lncRNA DGCR5 in malignant phenotype and immune infiltration of human cancers

As a special type of noncoding RNA, long noncoding RNAs (lncRNAs) have vital roles during the development of human cancers and may be novel predictors or therapeutic targets for improving the management of patients with cancer. DiGeorge syndrome critical region gene 5 (DGCR5) is a prominent tumor-associated lncRNA, exerting tumor suppressor or oncogenic roles in various cancers. Previous studies have reported that DGCR5 has low expression in most types of cancers but high expression in triple-negative breast cancer, gallbladder cancer, and lung cancer. And DGCR5 expression is related to many hallmarks of cancer types, including cell proliferation, invasion, migration, apoptosis, stemness, and therapeutic responsiveness. Additionally, the pivotal molecules involved in DGCR5 regulation of signaling pathways are attributed to cancer hallmarks related to the pathogenesis of different types of malignant tumors. Herein, we discuss the DGCR5 expression pattern in various types of tumor tissues and relationships between DGCR5 expression and immune cell infiltration and immune purity. We also review our current understanding of DGCR5 in carcinogenesis and its potential application as a prognostic biomarker or therapeutic target in human cancers.     

Accessories to the crime: functions of cells recruited to the tumor microenvironment

Mutationally corrupted cancer (stem) cells are the driving force of tumor development and progression. Yet, these transformed cells cannot do it alone. Assemblages of ostensibly normal tissue and bone marrow-derived (stromal) cells are recruited to constitute tumorigenic microenvironments. Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types. Their contributory functions to hallmark capabilities are increasingly well understood, as are the reciprocal communications with neoplastic cancer cells that mediate their recruitment, activation, programming, and persistence. This enhanced understanding presents interesting new targets for anticancer therapy.     

Targeting MET in cancer: rationale and progress

Uncontrolled cell survival, growth, angiogenesis and metastasis are essential hallmarks of cancer. Genetic and biochemical data have demonstrated that the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the tyrosine kinase MET, have a causal role in all of these processes, thus providing a strong rationale for targeting these molecules in cancer. Parallel progress in understanding the structure and function of HGF/SF, MET and associated signalling components has led to the successful development of blocking antibodies and a large number of small-molecule MET kinase inhibitors. In this Review, we discuss these advances, as well as results from recent clinical studies that demonstrate that inhibiting MET signalling in several types of solid human tumours has major therapeutic value.     

Differential effects of hypoxia on etoposide-induced apoptosis according to the cancer cell lines

Background  

It is more and more recognized that hypoxia plays a role in the resistance of cancer cells to chemotherapy. However, the mechanisms underlying this resistance still need deeper understanding. The aim of this study was to investigate the effect of hypoxia on this process since hypoxia is one of the hallmarks of tumor environment.     

Obesity: a perfect storm for carcinogenesis

Obesity-related cancers account for 40% of the cancer cases observed in the USA and obesity is overtaking smoking as the most widespread modifiable risk factor for carcinogenesis. Here, we use the hallmarks of cancer framework to delineate how obesity might influence the carcinogenic hallmarks in somatic cells. We discuss the effects of obesity on (a) sustaining proliferative signaling; (b) evading growth suppressors; (c) resisting cell death; (d) enabling replicative immortality; (e) inducing angiogenesis; (f) activating invasion and metastasis; (g) reprogramming energy metabolism; and (h) avoiding immune destruction, together with its effects on genome instability and tumour-promoting inflammation. We present the current understanding and controversies in this evolving field, and highlight some areas in need of further cross-disciplinary focus. For instance, the relative importance of the many potentially causative obesity-related factors is unclear for each type of malignancy. Even within a single tumour type, it is currently unknown whether one obesity-related factor consistently plays a predominant role, or if this varies between patients or, even in a single patient with time. Clarifying how the hallmarks are affected by obesity may lead to novel prevention and treatment strategies for the increasingly obese population.

     

Targeting cell death signalling in cancer: minimising ‘Collateral damage'

Targeting apoptosis for the treatment of cancer has become an increasingly attractive strategy, with agents in development to trigger extrinsic apoptosis via TRAIL signalling, or to prevent the anti-apoptotic activity of BCL-2 proteins or inhibitor of apoptosis (IAP) proteins. Although the evasion of apoptosis is one of the hallmarks of cancer, many cancers have intact apoptotic signalling pathways, which if unblocked could efficiently kill cancerous cells. However, it is becoming increasing clear that without a detailed understanding of both apoptotic and non-apoptotic signalling, and the key proteins that regulate these pathways, there can be dose-limiting toxicity and adverse effects associated with their modulation. Here we review the main apoptotic pathways directly targeted for anti-cancer therapy and the unforeseen consequences of their modulation. Furthermore, we highlight the importance of an in-depth mechanistic understanding of both the apoptotic and non-apoptotic functions of those proteins under investigation as anti-cancer drug targets and outline some novel approaches to sensitise cancer cells to apoptosis, thereby improving the efficacy of existing therapies when used in combination with novel targeted agents.     

How can cancer research be illuminated by brain research (and vice versa)?

Cancer and brain research have historically followed concrete pathways and converged mostly to studying brain cancer. Nowadays, the fields of neuro-oncology and neuroendocrine regulation of tumorigenesis are both emerging fields of intense research and promising applications. An increasing body of evidence suggests that somatic mutations in cancer-related genes are prevalent in several noncancerous brain disorders. These findings highlighting that certain aspects of cancer development/progression and pathologies of the nervous system share molecular alterations, could assist in elucidating the unique hallmarks of cancer and in cancer drugs repurposing for brain disorders. In so doing, identifying the commonalities in these conditions could be crucial not only for better understanding the basis of these pathologies but also for considering the previously underappreciated and/or neglected possibility of using drugs known to be effective in one type of pathology for the other type.     

CDK2 positively regulates aerobic glycolysis by suppressing SIRT5 in gastric cancer

Although significant progress has been made in the diagnosis and treatment of gastric cancer, the overall survival rate of the disease remains unchanged at approximately 20%‐25%. Thus, there is an urgent need for a better understanding of the molecular biology aspects of the disease in the hope of discovering novel diagnosis and treatment strategies. Recent years have witnessed decisive roles of aberrant cancer cell metabolism in the maintenance of malignant hallmarks of cancers, and cancer cell metabolism has been regarded as a novel target for the treatment of cancer. CDK2, a cell cycle‐dependent kinase that usually regulates cell cycle progression and the DNA damage response, is reported to be upregulated in many cancers. However, little is known about its role in cancer cell metabolism. In the present study, we showed that silencing CDK2 inhibited the aerobic glycolytic capacity of gastric cancer cell lines. Mechanism explorations showed that silencing CDK2 increased expression of the SIRT5 tumor suppressor. In addition, the physiological roles of SIRT5 in the regulation of proliferation and glycolysis were studied in gastric cancer cells. Taken together, the present study uncovered novel roles of the CDK2/SIRT5 axis in gastric cancer and suggests future studies concerning gastric cancer cell metabolism.     

Dysregulated pH: a perfect storm for cancer progression

Although cancer is a diverse set of diseases, cancer cells share a number of adaptive hallmarks. Dysregulated pH is emerging as a hallmark of cancer because cancers show a 'reversed' pH gradient with a constitutively increased intracellular pH that is higher than the extracellular pH. This gradient enables cancer progression by promoting proliferation, the evasion of apoptosis, metabolic adaptation, migration and invasion. Several new advances, including an increased understanding of pH sensors, have provided insight into the molecular basis for pH-dependent cell behaviours that are relevant to cancer cell biology. We highlight the central role of pH sensors in cancer cell adaptations and suggest how dysregulated pH could be exploited to develop cancer-specific therapeutics.     

The Legacy of Mesenchymal Stem Cells in Vindicating the Clonal Evolution Model of Cancer

Organogenesis and tumorigenesis seem to be followinga set pretty similar instructions and pathways and tumors,like any other organ, can be seen as the summation ofmany different cell types. However, unlike normal tissues,intercellular networks in cancer show high degreesof robustness and plasticity, employing other cellularnetworks in favor of their own growth1. The integratedhallmarks of cancer were first described by Hanahan andWeinberg in 20002, and was updated in 2011 by the samescientists3. They have described 10 hallmarks including:1) self-sufficiency in growth signals, 2) not responding toantigrowth signals, 3) unlimited proliferation, 4) resistingapoptosis, 5) genomic instability, 6) angiogenesis, 7)deregulated metabolism, 8) inflammation, 9) escapingimmune destruction, and 10) tissue invasion andmetastasis3, all of which have stood the test of time asbeing integral components of most forms of neoplasms.These unifying hallmarks are a reflection of the networkstructure of human cells dictating which genetic/epigeneticalterations are viable and in favor of tumor formationand progression. Among all the theories trying to explainthe origins and hallmarks of cancer since Hippocrates4,clonal evolution and the stem cell hypothesis are the twotheories that explain hallmarks of cancer the best5. Forthe purpose of this editorial our focus will be on the clonalevolution theory.     

Is Akt the “Warburg kinase”?—Akt-energy metabolism interactions and oncogenesis

The serine/threonine kinase Akt – also known as protein kinase B (PKB) – has emerged as one of the most frequently activated protein kinases in human cancer. In fact, most, if not all, tumors ultimately find a way to activate this important kinase. As such, Akt activation constitutes a hallmark of most cancer cells, and such ubiquity presumably connotes important roles in tumor genesis and/or progression. Likewise, the hypermetabolic nature of cancer cells and their increased reliance on “aerobic glycolysis”, as originally described by Otto Warburg and colleagues, are considered metabolic hallmarks of cancer cells. In this review, we address the specific contributions of Akt activation to the signature metabolic features of cancer cells, including the so-called “Warburg effect”.