Oncovirus and Aggressive Malignancy

Along with an increase in longevity and changes in lifestyle, the number of cancer cases has risen substantially. Researchers estimate that half of all types of cancer in the United States are preventable. Of these preventable cancers, 5% are caused by infectious agents. In low-to-middle income countries that percentage can be as high as 30%.

Of all infection-associated cancers, approximately 90% can be attributed to hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomaviruses (HPV), and the bacterium Helicobacter pylori. These 4 infectious agents alone contribute to 18% of the global cancer burden.

Oncoviruses and Cancer Progression

While it is widely known that infection with oncoviruses can increase the risk for developing cancer, it has only recently been suggested that oncoviruses can contribute to cancer progression. HBV, HCV, HPV, Epstein-Barr virus (EBV), and Kaposi sarcoma herpesvirus (KSHV) are the most epidemiologically relevant human oncoviruses, and researchers have begun to look more closely at their role in cancer progression.

The methods by which oncoviruses contribute to cancer progression are varied and complex. Barbara Grasiele Müller-Coan, DVM, MsC of São Paulo State University, Medical School of Botucau, Brazil, and colleagues, categorized these mechanisms into 3 broader categories:

• microenvironment tuning,
• phenotypic modification, and
• genetic instability.

Hepatitis C Virus

HCV stimulates chronic inflammation and higher levels of oxidative stress in infected livers, which causes its oncogenesis. The structural proteins HCV core (HCVc) and E1, along with the nonstructural viral protein NS3, have also been linked to liver carcinogenesis and tumor progression.

With 6 HCV genotypes and more than 50 subtypes, the oncogenic potential of HCV is variable. However, researchers have identified several ways in which HCV contributes to cancer progression, both directly and indirectly. HCV products induce cell migration, cell invasion, extracellular matrix remodeling, epithelial-to-mesenchymal transitions, and tumor angiogenesis.

In terms of its contribution to cancer progression, HCV augments the plasticity of the malignant cells, which can increase tumor heterogeneity. “This process is typically associated with abnormal TGF-β signaling, a key feature of [hepatocellular carcinoma] HCC and a major contributor to increased aggressiveness in a variety of other human cancers,” according to Ms. Müller-Coan and her colleagues. “Indeed, HCV can hijack TGF-β signaling, either mediated by HCVc or its nonstructural proteins, thus connecting HCV infection to liver fibrosis, cell transformation, and also progression of HCC.”

Hepatitis B Virus

In countries with intermediate or poor medical resources, approximately 60% of HCC cases can be attributed to HBV. The small regulatory, nonstructural HBC protein, HBx, contributes to oncogenesis by interfering with critical signaling pathways.

The interaction of HBV mRNA with mature miR-122 decreases miR-122 availability in HCC cells, which increases cell invasion. Researchers have also found that HBV-positive HCC tissues have significantly reduced the expression of miRs 18a and 148a, which is associated with increased tumorigenesis and invasion.

The integration of HBV DNA into the host genome may also contribute to tumor progression, but research is currently scarce.

Human Papillomavirus

Ms. Müller-Coan and colleagues note that, compared with herpesviruses, HPV is relatively genetically simple, which limits its potential contribution to cancers. “HPV proteins often elicit host immune responses,” they wrote. “Thus, it is plausible that HPV-infected malignant cells are subjected to higher immunological pressure, which may cause delayed progression behavior seen with some HPV-associated carcinomas.”

Instead, the metastatic potential of HPV-associated carcinomas seems to be linked to the accumulation of genomic alterations. These changes allow new cellular features that are associated with malignant behavior to express themselves.

Human Herpesviruses

There are only 2 herpesviruses that are formally acknowledged as being oncogenic in humans: EBV and KSHV.

EBV can alter the tumor microenvironment in ways that contribute to cancer progression. One study found that higher numbers of tumor-associated macrophages that express CCL18 were associated with higher nasopharyngeal carcinoma (NPC) histologic grade and tumor stage, higher frequency of nodal or distant metastasis, and increased EMT features in malignant cells.

Research has shown that EBV-related LMP1, several EBNAs, and viral miRNA-BARTs may increase the aggressiveness of NPC. More research is needed to determine how these same EBV products affect other cancers.

KSHV uses viral homologs of key cellular proteins to interfere with cellular pathways. It can also regulate endogenous miRNAs, such as miR-31, miR-221, and miR-222. KSHV changes cell phenotype, typically increasing the local availability of cytokine and growth factors. This allows neoplastic spindle cells, such as KSHV-associated Kaposi sarcoma (KS,) to become more proliferative, migratory, angiogenic, and invasive.

Organ Donation and Oncovirus Risk

With the significant role that oncoviruses play in cancer development and progression, reducing the number of viral infections can help cut down on cancer cases. However, other public health factors are at play. With the rise of the opioid crisis in the United States, HCV infections have increased significantly. Not only does this affect the risk for cancer in these patients, it can also affect patients in need of organ donations.

Although the benefits of organ donation are undeniable, new data from the US Centers for Disease Control and Prevention (CDC)’s Mortality and Morbidity Weekly Report point to a new trend that could have a significant impact on oncovirus-related cancers.

From 2010 to 2017, the number of deceased donors increased by 29.5%, from 7943 to 10,287. However, with this increase in donors, the researchers noted a significant upsurge in increased risk donors (IRDs). In 2010, 8.9% of donors (n=709) were classified as IRDs compared with 26.3% (n=2704) in 2017.

There were no significant changes in HBsAg or anti-HBc positivity from 2010 to 2017, while anti-HCV positivity increased from 15.9% to 21.6%. From 2015 to 2017, HCV RNA positivity increased from 8.6% to 15.7%.

“Identification of HBV, HCV, and HIV risk factors among organ donors is critical to mitigate transmission risk and ensure monitoring and appropriate treatment of recipients for post-transplant infection,” Winston E. Abara, MD, of the division of viral hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB, CDC, and colleagues wrote.

Summary and Clinical Applicability

In addition to causing cancer, oncoviruses can increase cancer aggressiveness through microenvironment tuning, phenotypic modification, and genetic instability. As these viruses become more prevalent, more research needs to be done to determine how to refine prognosis and develop new therapeutic strategies.

References

1. Abara WE, Collier MG, Moorman A, et al. Characteristics of deceased solid organ donors and screening results for hepatitis B, C, and human immunodeficiency viruses – United States, 2010-2017. MMWR Morb Mortal Wkly Rep. 2019;68(3):61-66.

2. Müller-Coan BG, Caetano BFR, Pagano JS, Elgui de Oliveria D. Cancer progression goes viral: the role of oncoviruses in aggressiveness of malignancies. Trends Cancer. 2019;4(7):485-498.