From infection to cancer: how DNA tumour viruses alter host cell central carbon and lipid metabolism

Infections cause 13% of all cancers globally, and DNA tumour viruses account for almost 60% of these cancers. All viruses are obligate intracellular parasites and hijack host cell functions to replicate and complete their life cycles to produce progeny virions. While many aspects of viral manipulation of host cells have been studied, how DNA tumour viruses manipulate host cell metabolism and whether metabolic alterations in the virus life cycle contribute to carcinogenesis are not well understood. In this review, we compare the differences in central carbon and fatty acid metabolism in host cells following infection, oncogenic transformation, and virus-driven cancer of DNA tumour viruses including: Epstein–Barr virus, hepatitis B virus, human papillomavirus, Kaposi''s sarcoma-associated herpesvirus and Merkel cell polyomavirus.     

Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-dependent manner

Secondary bacterial infections often complicate respiratory viral infections, but the mechanisms whereby viruses predispose to bacterial disease are not completely understood. We determined the effects of infection with respiratory syncytial virus (RSV), human parainfluenza virus 3 (HPIV-3), and influenza virus on the abilities of nontypeable Haemophilus influenzae and Streptococcus pneumoniae to adhere to respiratory epithelial cells and how these viruses alter the expression of known receptors for these bacteria. All viruses enhanced bacterial adhesion to primary and immortalized cell lines. RSV and HPIV-3 infection increased the expression of several known receptors for pathogenic bacteria by primary bronchial epithelial cells and A549 cells but not by primary small airway epithelial cells. Influenza virus infection did not alter receptor expression. Paramyxoviruses augmented bacterial adherence to primary bronchial epithelial cells and immortalized cell lines by up-regulating eukaryotic cell receptors for these pathogens, whereas this mechanism was less significant in primary small airway epithelial cells and in influenza virus infections. Respiratory viruses promote bacterial adhesion to respiratory epithelial cells, a process that may increase bacterial colonization and contribute to disease. These studies highlight the distinct responses of different cell types to viral infection and the need to consider this variation when interpreting studies of the interactions between respiratory cells and viral pathogens.     

Epstein-Barr virus: induction and control of cell transformation

Epstein-Barr virus (EBV), a ubiquitous human herpes virus, is associated with an increasing number of lymphoid and epithelial malignancies. The ability of the virus to establish life-long persistent infections and induce growth transformation is related to the function of a set of viral proteins that are variously expressed in both normal and malignant cells. Recent evidence indicates that these viral proteins are able to usurp cellular pathways that promote the cell growth and survival, while impairing anti-viral immune responses. Elucidation of the mechanisms by which EBV induces cell transformation and escapes host immune control provides the rational background for the design of new strategies of intervention for EBV-related malignancies.     

A “hit-and-run” affair – A possible link for cancer progression in virally driven cancers

BackgroundIt is well-known that certain cancers are caused by viruses. However, viral oncogenesis is complex and only a small fraction of the infected people develop cancer. Indeed, a number of environmental factors can contribute to virally infected cells developing cancer hallmarks, promoting tumorigenesis.Scope of reviewThe hit-and-run theory proposes that viruses facilitate the accumulation of mutations and promote genomic instability until the virus becomes dispensable for tumour maintenance. Indeed, several studies have reported viral genome, episome and/or oncogene loss in tumour cells without losing malignant phenotype.Major conclusionsThe current evidence supports the clear contribution of certain viruses to develop cancers. Importantly, the evidence supporting the sustained maintenance of malignancy after the loss of viral “presence” is sufficient to support the hit-and-run hypothesis of viral cancer development. Long-term tracking of vaccination outcome over the decades will test this theory.General significanceIf the hit-and-run theory is true, viruses might cause more cancers than previously thought and will have implications in the prevention of many cancers through implementing vaccination programs.     

Seminal plasma enhances cervical adenocarcinoma cell proliferation and tumour growth in vivo

Cervical cancer is one of the leading causes of cancer-related death in women in sub-Saharan Africa. Extensive evidence has shown that cervical cancer and its precursor lesions are caused by Human papillomavirus (HPV) infection. Although the vast majority of HPV infections are naturally resolved, failure to eradicate infected cells has been shown to promote viral persistence and tumorigenesis. Furthermore, following neoplastic transformation, exposure of cervical epithelial cells to inflammatory mediators either directly or via the systemic circulation may enhance progression of the disease. It is well recognised that seminal plasma contains an abundance of inflammatory mediators, which are identified as regulators of tumour growth. Here we investigated the role of seminal plasma in regulating neoplastic cervical epithelial cell growth and tumorigenesis. Using HeLa cervical adenocarcinoma cells, we found that seminal plasma (SP) induced the expression of the inflammatory enzymes, prostaglandin endoperoxide synthase (PTGS1 and PTGS2), cytokines interleukin (IL) -6, and -11 and vascular endothelial growth factor-A (VEGF-A). To investigate the role of SP on tumour cell growth in vivo, we xenografted HeLa cells subcutaneously into the dorsal flank of nude mice. Intra-peritoneal administration of SP rapidly and significantly enhanced the tumour growth rate and size of HeLa cell xenografts in nude mice. As observed in vitro, we found that SP induced expression of inflammatory PTGS enzymes, cytokines and VEGF-A in vivo. Furthermore we found that SP enhances blood vessel size in HeLa cell xenografts. Finally we show that SP-induced cytokine production, VEGF-A expression and cell proliferation are mediated via the induction of the inflammatory PTGS pathway.     

Redirecting oncolytic viruses: Engineering opportunists to take control of the tumour microenvironment

The transformation of healthy cells to malignant often drives them to become inherently susceptible to viral infection as a trade-off to achieve uninhibited growth and immune escape. Enter oncolytic viruses (OVs), an exciting class of viruses that specifically infect cancer cells, leaving healthy tissue unharmed. Unfortunately, there is more to this story. Tumours are much more than a group of cancer cells, the surrounding tumour microenvironment (TME) comprises a collection of cells which influence and nourish the development and spread of the tumour. While initially quite promising, OV therapy has been met with a myriad of barriers due to the unwelcoming nature of the TME. Riddled with immunosuppressive factors and physical barriers, many tumours have proven impenetrable by OVs. Herein, we review the diverse array of approaches being used to target each component of the TME from enhancing entry into specific tumour types, breaking through the dense tumour stroma, eliminating cancer stem cells, and activating the immune system. We highlight the value of combination approaches which have led to complete successes in several in vivo models, some of which have entered clinical development.     

Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

Major changes in intra- and extracellular pH homoeostasis are shared features of most solid tumours. These changes stem in large part from the metabolic shift of most cancer cells towards glycolytic metabolism and other processes associated with net acid production. In combination with oncogenic signalling and impact from factors in the tumour microenvironment, this upregulates acid-extruding plasma membrane transport proteins which maintain intracellular pH normal or even more alkaline compared with that of normal cells, while in turn acidifying the external microenvironment. Mounting evidence strongly indicates that this contributes significantly to cancer development by favouring e.g. cancer cell migration, invasion and chemotherapy resistance. Finally, while still under-explored, it seems likely that non-cancer cells in the tumour microenvironment also exhibit altered pH regulation and that this may contribute to their malignant properties. Thus, the physical tumour microenvironment and the cancer and stromal cells within it undergo important reciprocal interactions which modulate the tumour pH profile, in turn severely impacting on the course of cancer progression. Here, we summarize recent knowledge of tumour metabolism and the tumour microenvironment, placing it in the context of tumour pH regulation, and discuss how interfering with these properties may be exploited clinically.     

Cell polarity in morphogenesis and metastasis

Most human cancers arise either from epithelial cells or their progenitors. Epithelial cells possess a distinctive apical–basal polarity and loss of polarity is frequently assumed to be a common feature of cancer progression. In particular, cancer cell dissemination to ectopic sites, and metastatic growth at those sites, is often considered to require a mesenchymal transition in which the transformed epithelial cells lose their apical–basal polarity. However, many cancers retain epithelial characteristics, and until recently there has been little conclusive evidence for an involvement of the cell polarity machinery in tumour growth and metastasis. In this article, we discuss evidence that polarity proteins can be potent invasion suppressors but that loss of epithelial character is not essential either for tumour growth and invasion, or metastatic colonization.     

Novel Insights into Cell Entry of Emerging Human Pathogenic Arenaviruses

Viral hemorrhagic fevers caused by emerging RNA viruses of the Arenavirus family are among the most devastating human diseases. Climate change, global trade, and increasing urbanization promote the emergence and re-emergence of these human pathogenic viruses. Emerging pathogenic arenaviruses are of zoonotic origin and reservoir-to-human transmission is crucial for spillover into human populations. Host cell attachment and entry are the first and most fundamental steps of every virus infection and represent major barriers for zoonotic transmission. During host cell invasion, viruses critically depend on cellular factors, including receptors, co-receptors, and regulatory proteins of endocytosis. An in-depth understanding of the complex interaction of a virus with cellular factors implicated in host cell entry is therefore crucial to predict the risk of zoonotic transmission, define the tissue tropism, and assess disease potential. Over the past years, investigation of the molecular and cellular mechanisms underlying host cell invasion of human pathogenic arenaviruses uncovered remarkable viral strategies and provided novel insights into viral adaptation and virus–host co-evolution that will be covered in the present review.     

Combining oncolytic virotherapy and tumour vaccination

The interactions between the immune system, a malignant tumour and an oncolytic virus are complex and poorly understood. For oncolytic viruses to become successful therapeutics we need to better understand these interactions and identify strategies to take advantage of defects in the innate immune response within tumours and avoid cellular anti-viral responses while capitalizing on anti-tumoural immunity. In this review we will discuss the evidence for the induction of tumour-specific immune responses by oncolytic viruses as well as by cancer vaccines. We will then describe some of the barriers to successful cancer immunotherapy, and finally we will outline a strategy for enhancing anti-tumoural immunity while reducing anti-viral immunity by combining tumour vaccination with oncolytic viral therapy.     

Picornaviruses and cell death

Members of the picornavirus family, including poliovirus and foot-and-mouth disease virus, are widespread pathogens of humans and domestic animals. Recent global developments in the resurgence of poliovirus infection and in the control of foot-and-mouth disease infection highlight the problems caused by the ability of picornaviruses to alter the apoptotic machinery of host cells and establish persistent infections. Despite the medical, economic and social impact of this family of viruses, little information exists that integrates the mechanisms of cell death and damage induced by related family members. Fortunately, examination of the reported roles and functions of individual viral proteins from multiple picornaviruses makes it possible to surmise canonical functions for these proteins. This review analyzes the canonical function of picornavirus proteins involved in the alteration of apoptotic homeostasis in infected host cells.     

From Scourge to Cure: Tumour-Selective Viral Pathogenesis as a New Strategy against Cancer

Tumour mutations corrupt cellular pathways, and accumulate to disrupt, dysregulate, and ultimately avoid mechanisms of cellular control. Yet the very changes that tumour cells undergo to secure their own growth success also render them susceptible to viral infection. Enhanced availability of surface receptors, disruption of antiviral sensing, elevated metabolic activity, disengagement of cell cycle controls, hyperactivation of mitogenic pathways, and apoptotic avoidance all render the malignant cell environment highly supportive to viral replication. The therapeutic use of oncolytic viruses (OVs) with a natural tropism for infecting and subsequently lysing tumour cells is a rapidly progressing area of cancer research. While many OVs exhibit an inherent degree of tropism for transformed cells, this can be further promoted through pharmacological interventions and/or the introduction of viral mutations that generate recombinant oncolytic viruses adapted to successfully replicate only in a malignant cellular environment. Such adaptations that augment OV tumour selectivity are already improving the therapeutic outlook for cancer, and there remains tremendous untapped potential for further innovation.     

A virus causes cancer by inducing massive chromosomal instability through cell fusion

Chromosomal instability (CIN) underlies malignant properties of many solid cancers and their ability to escape therapy, and it might itself cause cancer [1, 2]. CIN is sustained by deficiencies in proteins, such as the tumor suppressor p53 [3-5], that police genome integrity, but the primary cause of CIN in sporadic cancers remains uncertain [6, 7]. The primary suspects are mutations that deregulate telomere maintenance, or mitosis, yet such mutations have not been identified in the majority of sporadic cancers [6]. Alternatively, CIN could be caused by a transient event that destabilizes the genome without permanently affecting mechanisms of mitosis or proliferation [5, 8]. Here, we show that an otherwise harmless virus rapidly causes massive chromosomal instability by fusing cells whose cell cycle is deregulated by oncogenes. This synergy between fusion and oncogenes "randomizes" normal diploid human fibroblasts so extensively that each analyzed cell has a unique karyotype, and some produce aggressive, highly aneuploid, heterogeneous, and transplantable epithelial cancers in mice. Because many viruses are fusogenic, this study suggests that viruses, including those that have not been linked to carcinogenesis, can cause chromosomal instability and, consequently, cancer by fusing cells.     

Hazara virus and Crimean-Congo Hemorrhagic Fever Virus show a different pattern of entry in fully-polarized Caco-2 cell line

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) and Hazara virus (HAZV) belong to the same viral serotype and family. HAZV has lately been used as a model system and surrogate to CCHFV. However, virus-host cell interaction and level of pathogenicity for these viruses are not well investigated nor compared. In this study, we compared HAZV and CCHFV infection of human polarized epithelial cells to shed light on similarities and differences in virus-host cell interaction between these two viruses. We investigated the pattern of infection of CCHFV and HAZV in fully polarized human cells, the Caco-2 cell line. Polarization of Caco-2 cells lead to difference in expression level and pattern of proteins between the apical and the basolateral membranes. We found that CCHFV virus, in contrast to HAZV, is more likely infecting polarized cells basolaterally. In addition, we found that cytokines/pro-inflammatory factors or other viral factors secreted from CCHFV infected moDC cells enhance the entry of CCHFV contrary to HAZV. We have shown that CCHFV and HAZV early in infection use different strategies for entry. The data presented in this study also highlight the important role of cytokines in CCHFV-host cell interaction.     

Mesenchymal stem cells promote cell invasion and migration and autophagy‐induced epithelial‐mesenchymal transition in A549 lung adenocarcinoma cells

Mesenchymal stem cells (MSCs) are recruited into the tumour microenvironment and promote tumour growth and metastasis. Tumour microenvironment‐induced autophagy is considered to suppress primary tumour formation by impairing migration and invasion. Whether these recruited MSCs regulate tumour autophagy and whether autophagy affects tumour growth are controversial. Our data showed that MSCs promote autophagy activation, reactive oxygen species production, and epithelial‐mesenchymal transition (EMT) as well as increased migration and invasion in A549 cells. Decreased expression of E‐cadherin and increased expression of vimentin and Snail were observed in A549 cells cocultured with MSCs. Conversely, MSC coculture‐mediated autophagy positively promoted tumour EMT. Autophagy inhibition suppressed MSC coculture‐mediated EMT and reduced A549 cell migration and invasion slightly. Furthermore, the migratory and invasive abilities of A549 cells were additional increased when autophagy was further enhanced by rapamycin treatment. Taken together, this work suggests that microenvironments containing MSCs can promote autophagy activation for enhancing EMT; MSCs also increase the migratory and invasive abilities of A549 lung adenocarcinoma cells. Mesenchymal stem cell‐containing microenvironments and MSC‐induced autophagy signalling may be potential targets for blocking lung cancer cell migration and invasion.