Curr Pharmacol Rep (2017) 3:315–320 DOI 10.1007/s40495-017-0109-y IMMUNOLOGY AND INFLAMMATION (W GAUSE AND L COVEY, SECTION EDITORS) Infection: a Cause of and Cure for Cancer Jenna H. Newman1 & Andrew Zloza1,2 Published online: 5 October 2017 # The Author(s) 2017. This article is an open access publication Abstract pathogens so that anti-pathogen immune responses can be Purpose of Review This article provides a brief overview of harnessed as a transformative means to treat cancer. the role that infections play in cancer emergence and cancer treatment. Keywords Infection . Inflammation . Pathogen . Cancer . Recent Findings A select number of pathogens have been Oncolytic . Oncogenic . Non-oncolytic . Non-oncogenic reported to increase the incidence of specific cancers (directly through altering gene expression or indirectly through induc- ing chronic inflammation). These have been referred to as Introduction oncogenic pathogens. Conversely, a subset of pathogens has been demonstrated to preferentially cause lysis of tumor cells, Case reports dating to the ancient past and more recent epide- leading to tumor regression and improved anti-tumor immu- miological studies have described both a positive and negative nity. These have been termed oncolytic pathogens. However, role for infection in the context of cancer (Fig. 1). In ancient the contribution of non-oncogenic, non-oncolytic pathogens Egypt, a physician named Imhotep reported regression of tu- to both tumor growth and regression is likewise being increas- mors in which infection was initiated by making an incision at ingly recognized. the tumor site [1]. Similar reports emerged throughout the first Summary Pathogens have both the ability to cause and cure millennium, but remained isolated observations until cancer. However, the mechanisms underlying these pathogen- American physician William Coley, inspired by earlier reports mediated outcomes are not fully understood. With the recent and his own observations, began to systematically study the emergence of interest in the immunotherapy of cancer, it is relationship between infection and tumor regression in the late important that future studies focus specifically on preventing nineteenth century [1]. In 1891, Coley observed the complete the negative effects of oncogenic infections, deconstructing regression of a sarcoma after failure of a surgical wound to the positive role of oncolytic pathogens, and finally providing close [1]. Coley hypothesized that this regression was enabled insight into the dual roles of non-oncolytic, non-oncogenic by the patient’s febrile erysipelas infection, caused by the bac- terium Streptococcus pyogenes [1]. After conducting a series This article is part of the Topical Collection on Immunology and of experiments, Coley developed a vaccine that harbored Inflammation toxins from killed Streptococcus pyogenes and Serratia marcescens bacteria [1]. With variable success across patients, * Andrew Zloza Coley’s approach waned in popularity upon the advent of [email protected] radiation and chemotherapy as cancer treatments [1]. However, interest in the positive role that infections can play 1 Section of Surgical Oncology Research, Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, 195 Little Albany in tumor regression has experienced resurgence in recent years Street, New Brunswick, NJ 08903, USA with the discovery that some pathogens, specifically oncolytic 2 Department of Surgery, Rutgers Robert Wood Johnson Medical viruses, can preferentially replicate and lyse cancer cells [2]. School, Rutgers, The State University of New Jersey, 675 Hoes Lane In the early twentieth century, evidence for a link between West, Piscataway Township, NJ 08854, USA infection and cancer was made when growth of human warts 316 Curr Pharmacol Rep (2017) 3:315–320 Fig. 1 Role of infections in cancer. This schematic describes the manner in which oncogenic, NON-ONCOLYTIC, oncolytic, and non-oncogenic, ONCOGENIC ONCOLYTIC NON-ONCOGENIC, non-oncolytic pathogens affect PATHOGENS PATHOGENS cancer formation and cancer PATHOGENS regression Viral replication Integration of viral Concomitant viral occurs preferentially genome into host infection and cancer in tumors genome may lead to accelerated tumor Release of tumor Promotion of host growth and cancer- neoantigens, cell replication specific death OR cytokines, viral tumor regression PAMPs and DAMPs upon tumor cell lysis Chronic inflammation Mechanisms are currently unknown Systemic immune Immunosuppression activation CANCER CANCER FORMATION REGRESSION and chicken leukemia could be initiated in naïve hosts subse- highlight emerging interest in the role of non-oncolytic, non- quent to transfer of cell-free extracts from lesions of afflicted oncogenic pathogens in cancer progression and treatment. hosts [3–5]. However, due to the fact that leukemia was not considered to be a malignancy at the time of publishing, these results were overlooked. Upon realization that a component of Oncogenic Viruses a cell-free extract (virus particles) could trigger the develop- ment of cancer in a recipient animal, the concept of oncogenic In 1911, Rockefeller Institute (now Rockefeller University in (cancer-causing) viruses emerged. Throughout the twentieth New York City) pathologist Francis Peyton Rous demonstrat- century, dozens of oncogenic viruses, many employing dis- ed that sarcomas developed in chickens that were adminis- tinct mechanisms to promote cancer development, were iden- tered supernatant of tumor extracts from sarcomas originating tified. As there has been growing understanding of the com- in other chickens of the same variety [7]. Tumor extracts were plex relationship between infection and cancer, it has become suspended in sterile sand and Ringer’s solution and subjected clear that infection with non-oncogenic, non-oncolytic patho- to multiple rounds of centrifugation, convincing Rous that gens can impact tumor growth. For instance, it has been re- tumor extracts injected into naïve animals were indeed cell- ported that patients afflicted with non-gastrointestinal acute free [7]. Rous proposed that the transmissible, cancer-causing bacterial infections exhibited higher rates of colon cancer- agent was a Bminute parasitic organism^ or a Bchemical stim- specific death compared to those without bacterial illness [6]. ulant elaborated by the neoplastic cells^ [7]. However, con- Although conflicting reports regarding the role of infection temporaries dismissed these ideas and insisted that the tumor in tumor development and cancer cure exist, it is widely ac- extracts were not completely cell-free and/or that the masses cepted that a select group of pathogens increase the incidence Rous identified were infectious granulomata rather than tu- of cancer (oncogenic pathogens) and that a select group of mors [3]. The importance of the Rous sarcoma virus (RSV), pathogens preferentially lyse tumor cells and lead to tumor cancer-causing agent derived from the cell-free supernatant of regression (oncolytic pathogens). However, it should be noted chicken tumor extracts, was overlooked until 1958, when that while select pathogens may curtail tumor growth, to our Howard Temin and Harry Rubin demonstrated that RSV knowledge, no viral infection has been shown to prevent can- could convert a chicken fibroblast into a cell with an embry- cer in humans. In this review, we focus on the role of these two onic cell phenotype [3, 8]. This key experiment brought forth subsets of pathogens in the cause and cure of cancer and a revival of the study of RSV, and Rous was awarded the Curr Pharmacol Rep (2017) 3:315–320 317 Nobel Prize in Physiology and Medicine in 1966 [3]. In 1970, Nevertheless, the inflammation brought forth by chronic in- Howard Temin, Satoshi Mizutani, and David Baltimore dis- fection is a clinically significant mechanism of oncogenic covered that the RSV virion harbored an RNA-dependent virus-mediated tumorigenesis. In fact, inflammation as a me- DNA polymerase, in addition to its single-stranded RNA ge- diator of cancer development is not limited to oncogenic viral nome [9, 10]. Viruses possessing the capability of converting infection. Individuals with Crohn’s disease have an elevated RNA to DNA, now called retroviruses, were later shown to risk of developing colorectal cancer [21], and those infected use an enzyme called integrase to insert viral DNA into the with the bacterium Helicobacter pylori are at higher risk than host genome [11]. RSV was found to contain in its genome an the general population for developing stomach cancer [22]. avian-derived oncogene [12], src, and the integration of src While commonly referenced as classic mechanisms by into a host cell genome was demonstrated to be the mechanis- which viruses can cause cancer, retroviral integration into tic driver of oncogenesis by RSV [13]. Apart from such inte- the host genome and inflammation and cell turnover caused gration of a host cell-derived oncogene into the host genome, by chronic viral infection are only two of the several mecha- it has been widely acknowledged that another mechanism of nisms by which viral infection can impact tumor development. retroviral-induced carcinogenesis is integration of the viral Epstein-Barr virus (EBV) has been linked to nasopharyngeal genome in regions of proto-oncogenes or tumor suppressor carcinoma and several subtypes of lymphoma, including genes. Disruptions in such genes may yield hyperactivity of Burkitt’s lymphoma and Hodgkin’slymphoma[23 ].