Posts Tagged ‘cancer’

From Scourge to Cure: Viruses Versus Cancer

Thursday, February 13th, 2014

Oncolytic Viruses I’m hoping to have a final year student working with me next year on a project about oncolytic viruses. This short review is a very nice overview of this developing field:

“With [oncolytic viruses] OV cancer therapeutics entering advanced-stage trials and showing clinical efficacy, strategies that further broaden OV targeting and replication capacity to address the heterogeneous nature of tumours and their associated vascular and stromal architecture will be extremely useful. Since such heterogeneity not only exists between patients but also within a given tumour/patient, where the metabolism, signal transduction, and antiviral states of cancer cells can be variably abnormal and, therefore, variably support OV replication, combinatorial strategies will be essential to promoting reliable tumour control and regression. Finally, continued efforts to identify components innate to the complex tumour microenvironment that promote OV replication will be critical to further improving OVs and developing new engineering strategies.”

From Scourge to Cure: Tumour-Selective Viral Pathogenesis as a New Strategy against Cancer. (2014) PLoS Pathog 10(1): e1003836. doi:10.1371/journal.ppat.1003836
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.

 

Diseases associated with human papillomavirus infection

Thursday, September 26th, 2013

Genital wart The papillomaviridae are ancient and ubiquitous viruses, with over 200 types of species-specific viruses classified into 16 genera. Papillomaviruses preferentially infect differentiating squamous epithelium and in humans, and almost every part of human skin can be infected. HPV was the first known human tumour virus, associated with benign, epithelial proliferations or papillomas and there are now 120 different HPV types officially recognised with others pending classification. In recent decades, the causal association of HPV with cervical cancer, but also with an increasing number of squamous cell carcinomas at specific sites, has been recognised. This paper sets out the range of infections and clinical manifestations of the consequences of infection and its persistence.

The range of infections, precancers and malignancies associated with HPV continues to grow. While much effort worldwide focusses on the potential to eradicate cervical cancer by HPV vaccination programmes targeting pre-sexually active girls, the burden of disease is increasing in other areas, particularly with the high prevalence of genital warts and of anal and oropharyngeal cancers, in both men and women. It is important also to recognise the morbidity of cutaneous HPV lesions, particularly in the immunosuppressed population. HPVs remain both highly effective pathogens and carcinogens, well adapted to their ecological niches, capable of avoiding immune responses and therefore challenging to eliminate.

 

Diseases associated with human papillomavirus infection. (2013) Virology pii: S0042-6822(13)00356-5. doi: 10.1016/j.virol.2013.06.007
Human papillomaviruses (HPVs) are ubiquitous, well adapted to their host and cleverly sequestered away from immune responses. HPV infections can be productive, subclinical or latent in both skin and mucosa. The causal association of HPV with cervical cancer, and increasingly with rising numbers of squamous cell carcinomas at other sites in both men and women, is increasingly recognised, while the morbidity of cutaneous HPV lesions, particularly in the immunosuppressed population is also significant. This chapter sets out the range of infections and clinical manifestations of the consequences of infection and its persistence and describes why HPVs are both highly effective pathogens and carcinogens, challenging to eliminate.

Could bacteria give you cancer?

Monday, July 29th, 2013

Fusobacterium Is Associated with Colorectal Cancer We know of at least eight viruses which cause cancer in humans, but apart from Helicobacter pylori there are no firmly established cases of bacteria causing tumours. Having said that, there are a number of bacteria which have been shown to be associated with certain cancers, but the relationship between cancer and bacteria is not as clear cut as in the casue of human tumour viruses. A recent paper in PLOS ONE adds to the list of bacteria associated with particular tumours.

The human intestinal microbiota inhabits a complex and diverse environment populated by hundreds of different bacterial species. These bacteria are regulated in the gut by the mucosal immune system, which is made up of a complex network of functions and immune responses aimed at maintaining a cooperative system between the intestinal microbiota and the host. In a healthy gut these bacteria maintain homeostasis with the host. However, when an imbalance, or bacterial dysbiosis, occurs in the gut, the host may experience inflammation and a loss of barrier function. Bacterial dysbioses have been linked to several diseases including ulcerative colitis, Crohn’s disease and colorectal cancer (CRC).

No single bacterial species has been identified as a risk factor for CRC, but recent studies report an increase in the abundance of Fusobacterium in human colorectal tumors compared to controls. These studies suggest that Fusobacterium may be associated with the later stages of CRC, but it is unknown if they play a role in the early stages of colorectal carcinogenesis. While the causes of colorectal cancer are not fully known, it is becoming increasingly clear that the gut microbiota provide an important contribution.

 

Fusobacterium Is Associated with Colorectal Adenomas. (2013) PLoS ONE 8(1): e53653. doi:10.1371/journal.pone.0053653
The human gut microbiota is increasingly recognized as a player in colorectal cancer (CRC). While particular imbalances in the gut microbiota have been linked to colorectal adenomas and cancer, no specific bacterium has been identified as a risk factor. Recent studies have reported a high abundance of Fusobacterium in CRC subjects compared to normal subjects, but this observation has not been reported for adenomas, CRC precursors. We assessed the abundance of Fusobacterium species in the normal rectal mucosa of subjects with (n = 48) and without adenomas (n = 67). We also confirmed previous reports on Fusobacterium and CRC in 10 CRC tumor tissues and 9 matching normal tissues by pyrosequencing. We extracted DNA from rectal mucosal biopsies and measured bacterial levels by quantitative PCR of the 16S ribosomal RNA gene. Local cytokine gene expression was also determined in mucosal biopsies from adenoma cases and controls by quantitative PCR. The mean log abundance of Fusobacterium or cytokine gene expression between cases and controls was compared by t-test. Logistic regression was used to compare tertiles of Fusobacterium abundance. Adenoma subjects had a significantly higher abundance of Fusobacterium species compared to controls (p = 0.01). Compared to the lowest tertile, subjects with high abundance of Fusobacterium were significantly more likely to have adenomas (OR 3.66, 95% CI 1.37–9.74, p-trend 0.005). Cases but not controls had a significant positive correlation between local cytokine gene expression and Fusobacterium abundance. Among cases, the correlation for local TNF-α and Fusobacterium was r = 0.33, p = 0.06 while it was 0.44, p = 0.01 for Fusobacterium and IL-10. These results support a link between the abundance of Fusobacterium in colonic mucosa and adenomas and suggest a possible role for mucosal inflammation in this process.

Modulation of apoptosis by oncogenic viruses

Tuesday, June 11th, 2013

Apoptosis Hmm, this sounds like a good exam question for next year’s paper. I wonder if any of my students read this blog? ;-)

 

The modulation of apoptosis by oncogenic viruses. (2013) Virology Journal, 10: 182 doi:10.1186/1743-422X-10-182
Transforming viruses can change a normal cell into a cancer cell during their normal life cycle. Persistent infections with these viruses have been recognized to cause some types of cancer. These viruses have been implicated in the modulation of various biological processes, such as proliferation, differentiation and apoptosis. The study of infections caused by oncogenic viruses had helped in our understanding of several mechanisms that regulate cell growth, as well as the molecular alterations leading to cancer. Therefore, transforming viruses provide models of study that have enabled the advances in cancer research. Viruses with transforming abilities, include different members of the Human Papillomavirus (HPV) family, Hepatitis C virus (HCV), Human T-cell Leukemia virus (HTLV-1), Epstein Barr virus (EBV) and Kaposi’s Sarcoma Herpesvirus (KSHV).Apoptosis, or programmed cell death, is a tightly regulated process that plays an important role in development and homeostasis. Additionally, it functions as an antiviral defense mechanism. The deregulation of apoptosis has been implicated in the etiology of diverse diseases, including cancer. Oncogenic viruses employ different mechanisms to inhibit the apoptotic process, allowing the propagation of infected and damaged cells. During this process, some viral proteins are able to evade the immune system, while others can directly interact with the caspases involved in apoptotic signaling. In some instances, viral proteins can also promote apoptosis, which may be necessary for an accurate regulation of the initial stages of infection.

Just WTF does HBV X actually do?

Thursday, May 30th, 2013

HBV-infected cells Chronic hepatitis B virus (HBV) infection is a worldwide health problem, and it has become one of the major causes of end-stage liver disease, including cirrhosis and hepatocellular carcinoma (HCC). In the past decade, the crucial role of HBV in hepatocarcinogenesis has been well established, but the mechanisms underlying how HBV induces malignant transformation of hepatocytes remains unclear. HBV X (HBx) is a 154-amino-acid (154-aa) multifunctional protein that has roles in gene transcription, cell proliferation, and apoptosis. For a long time, HBx has been suspected of playing positive roles in hepatocarcinogenesis, possibly by affecting viral replication and viral proliferation directly or indirectly.

In an attempt to fully understand the role of environmental factors on HBx protein in regulating HBV transcription and replication, researchers used two different cell culture systems in vitro and an immunocompetent HBV replication mouse model in vivo. Moreover, we sought to verify roles of the transcriptional transactivation regions in the C-terminal transactivation domain of HBx in modulating the levels of HBV transcription and replication under physiological conditions in vivo.

HBx was found to be required for wild-type levels of HBV replication in HepG2 cells, but was not essential for the establishment of HBV replication in Huh7 cells, indicating that the effects of HBx on HBV replication and transcription vary depending on the experimental system. No wonder there is confusion about the role(s) of the X protein. In contrast to in vivo experiments, HBx has an important role in stimulating HBV transcription and replication in hepatocytes in vivo. The transcriptional transactivation function of HBx may be crucial for its stimulatory effect on HBV transcription and replication.

 

Role and Functional Domain of Hepatitis B Virus X Protein in Regulating HBV Transcription and Replication in Vitro and in Vivo. Viruses 2013, 5(5), 1261-1271; doi:10.3390/v5051261
The role of hepatitis B virus (HBV) X protein (HBx) in the regulation of HBV replication remains controversial. In the present study, the role of HBx in regulating HBV replication was initially investigated in both HepG2 and Huh7 in vitro cell lines with a transient transfection system. Next, the regions of HBx responsible for transcriptional transactivation and promotion of HBV replication were mapped in an HBV replication mouse model by in vivo transfection of a series of HBx expression plasmids. In an in vitro setting, HBx deficiency had little effect on HBV replication in Huh7 cells, but impaired HBV replication in HepG2 cells. In an in vivo setting, HBx had a strong enhancing effect on HBV transcription and replication. For the C-terminal two-thirds of the protein (amino acids [aa] 51 to 154) was required for this function of HBx, and the regions spanning aa 52 to 72 and 88 to 154 were found to be important for the stimulatory function of HBx on HBV replication. In conclusion, the role of HBx in HBV replication regulation is affected by host cell type, and HBx has an important role in stimulating HBV transcription and replication in hepatocytes in vivo. Further, the transcriptional transactivation function of HBx may be crucial for its stimulatory effect on HBV transcription and replication.

 

Plucking hell – your eyebrows are full of viruses

Monday, April 29th, 2013

Eyebrow Actinic keratosis is no laughing matter – untreated, up to 20% of cases may pregress to skin cancer. At the same time, if this paper had been published on 1st April (it wasn’t) I would have had my doubts. I’ve seen some interesting virus sampling protocols in my time (bear in mind we sequenced the horse faeces virome), but this one is pretty unique. As a side benefit, also reduces the risk of monobrow.

 

Eyebrow hairs from actinic keratosis patients harbor the highest number of cutaneous human papillomaviruses. BMC Infectious Diseases 2013, 13: 186 doi:10.1186/1471-2334-13-186
Cutaneous human papillomavirus (HPV) infections seem to be associated with the onset of actinic keratosis (AK). This study compares the presence of cutaneous HPV types in eyebrow hairs to those in tissues of normal skin and skin lesions of 75 immunocompetent AK patients. Biopsies from AK lesions, normal skin and plucked eyebrow hairs were collected from each patient. DNA from these specimens was tested for the presence of 28 cutaneous HPV (betaPV and gammaPV) by a PCR based method. The highest number of HPV prevalence was detected in 84% of the eyebrow hairs (63/75, median 6 types) compared to 47% of AK lesions (35/75, median 3 types) (p< 0.001) and 37% of normal skin (28/75, median 4 types) (p< 0.001), respectively. A total of 228 HPV infections were found in eyebrow hairs compared to only 92 HPV infections in AK and 69 in normal skin. In all three specimens HPV20, HPV23 and/or HPV37 were the most prevalent types. The highest number of multiple types of HPV positive specimens was found in 76% of the eyebrow hairs compared to 60% in AK and 57% in normal skin. The concordance of at least one HPV type in virus positive specimens was 81% (three specimens) and 88-93% of all three combinations with two specimens. Thus, eyebrow hairs revealed the highest number of cutaneous HPV infections, are easy to collect and are an appropriate screening tool in order to identify a possible association of HPV and AK.

 

The Rapidly Expanding Family of Human Polyomaviruses

Wednesday, March 20th, 2013

Human Polyomaviruses Since their discovery in 1971, the polyomaviruses JC (JCPyV) and BK (BKPyV), isolated from patients with progressive multifocal leukoencephalopathy and polyomavirus-associated nephropathy, respectively, remained for decades as the only known members of the Polyomaviridae family of viruses of human origin. Over the past five years, the application of new genomic amplification technologies has facilitated the discovery of several novel human polyomaviruses (HPyVs), bringing the present number to 10. These HPyVs share many fundamental features in common such as genome size and organization. Infection by all HPyVs is widespread in the human population, but they show important differences in their tissue tropism and association with disease. Much remains unknown about these new viruses.
This review discusses the problems associated with studying HPyVs, such as the lack of culture systems for the new viruses and the gaps in our basic understanding of their biology, and summarizes what is known so far about their distribution, life cycle, tissue tropism, their associated pathologies (if any), and future research directions.
The Rapidly Expanding Family of Human Polyomaviruses: Recent Developments in Understanding Their Life Cycle and Role in Human Pathology. (2013) PLoS Pathog 9(3): e1003206. doi:10.1371/journal.ppat.1003206

 

Until a few years ago the polyomavirus family (Polyomaviridae) included a dozen viruses identified in avian and mammal hosts. Two of these, the JC and BK-polyomaviruses isolated long time ago, are known to infect humans and cause severe illness in immunocompromized hosts. Since 2007 an unprecedented number of eight new polyomaviruses was discovered in humans. Among them are the KI and WU-polyomaviruses identified in respiratory samples, the Merkel cell polyomavirus found in skin carcinomas, and the polyomavirus associated with trichodysplasia spinulosa, a skin disease of transplant patients. Another four new human polyomaviruses were identified, HPyV6, HPyV7, HPyV9, and the Malawi polyomavirus, so far not associated with any disease. In the same period several new mammal polyomaviruses were described.
This review summarizes the recent developments in studying the new human polyomaviruses, and touches upon several aspects of polyomavirus virology, pathogenicity, epidemiology and phylogeny.
From Stockholm to Malawi: recent developments in studying human polyomaviruses. J Gen Virol. 19 Dec 2012

 

Mystery of Hepatitis B Virus and cancer solved? 

Thursday, January 17th, 2013

Exactly how hepatitis B virus causes liver cancer has been a mystery for a long time. It is clear that the X protein (HBx) has something to do with it, but exactly what mechanisms are involved?  These are very different to other cancer-causing viruses.

Some recent studies have demonstrated that viruses alter the expression of microRNAs, non-coding RNA molecules that can block the expression of target genes. Researchers have just reported that miR-148a is repressed by HBx to promote growth and metastasis of liver cancer. In normal liver cells, miR-148a represses the expression of the oncogenic protein HPIP, but the hepatitis B virus prevents expression of miR-148a, leading to increased levels of HPIP and subsequent oncogenic transformation. This study demonstrates that a cancer-associated virus promotes carcinogenesis through direct manipulation of a microRNA.

Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis: http://goo.gl/2HkK7
Abstract: MicroRNAs (miRNAs) have been shown to be dysregulated in virus-related cancers; however, miRNA regulation of virus-related cancer development and progression remains poorly understood. Here, we report that miR-148a is repressed by hepatitis B virus (HBV) X protein (HBx) to promote cancer growth and metastasis in a mouse model of hepatocellular carcinoma (HCC). Hematopoietic pre–B cell leukemia transcription factor–interacting protein (HPIP) is an important regulator of cancer cell growth. We used miRNA target prediction programs to identify miR-148a as a regulator of HPIP. Expression of miR-148a in hepatoma cells reduced HPIP expression, leading to repression of AKT and ERK and subsequent inhibition of mTOR through the AKT/ERK/FOXO4/ATF5 pathway. HBx has been shown to play a critical role in the molecular pathogenesis of HBV-related HCC. We found that HBx suppressed p53-mediated activation of miR-148a. Moreover, expression of miR-148a was downregulated in patients with HBV-related liver cancer and negatively correlated with HPIP, which was upregulated in patients with liver cancer. In cultured cells and a mouse xenograft model, miR-148a reduced the growth, epithelial-to-mesenchymal transition, invasion, and metastasis of HBx-expressing hepatocarcinoma cells through inhibition of HPIP-mediated mTOR signaling. Thus, miR-148a activation or HPIP inhibition may be a useful strategy for cancer treatment.

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Nature Outlook – human papillomavirus

Friday, August 31st, 2012

xxx Nature has just published an excellent supplement (free full access) on human papillomavirus. The new material is medical rather than biological in slant, covering vaccination and diagnostic tests rather than the basic biology of HPV, but still well worth a look:

 

Nature Outlook – human papillomavirus. (2012) Nature Vol. 488 No. 7413_supp ppS1-S48