Biological carcinogenesis
The role of infectious agents in the development of cancer was intensively studied during the 1970s, and mechanisms of carcinogenesis were delineated. Worldwide, less than 20% of all cancers are related to infectious agents; however, this minority cause of cancer is mostly preventable.
Broadly, biological carcinogens can support tumor cell initiation and promotion either directly, as is the case for viral infections, or indirectly, such as with bacterial or parasitic infections that drive chronic inflammation and oxidative injury within the pathogen-host microenvironment. With respect to pathogens indirectly causing cancer in human beings, such as Helicobacter pylori and mucosa-associated lymphoid tissue lymphoma or Schistosoma haematobium and squamous cell carcinoma of the bladder, chronic inflammation with the consequent generation of reactive oxygen species strongly participates in the carcinogenic process (Ohshima & Bartsch, 1994). Similarly, in dogs, a strong association for esophageal sarcoma development because of chronic inflammation secondary to Spirocerca lupi infection has been reported by several independent investigations (Bailey, 1963; Dvir et al., 2010; Ranen et al., 2004; Ribelin and Bailey, 1958). Additionally, in felines, traumatic rupture of the eye orbit with the release of protected antigens has been reported to drive chronic inflammation and subsequent post-traumatic sarcoma development (Wood & Scott, 2019). Recently, some investigations have tried to link bartonellosis with the development of canine lymphoma and hemangiosarcoma, while Bartonella spp. DNA was identified in tumor tissues, a cause-and-effect could not be established and it remains uncertain what role arthropod vector diseases might play in malignant transformation or risk in dogs (Duncan et al., 2008; Lashnits et al., 2020).Unlike other infectious agents, the oncologic pathogenesis of viral infections is not reliant on the generation of chronic inflammation, but rather on the direct integration of viral genetic information into susceptible host cells.
Tumor viruses can be categorized as retroviruses or DNA viruses, with their mechanisms of carcinogenesis being distinct. Retroviruses can be categorized as acute transforming and late transforming, which depicts the expected latency period between viral infection and the development of cancer. Acute transforming retroviruses contain viral oncogenes (v-onc), and upon infection of susceptible cells, transcription of v-onc genes results in the immediate dysregulation of proto-oncogene functions (see Oncogenes) and consequent malignant transformation. Late transforming retroviruses do not carry viral oncogenes, and the dysregulation of normal proto-oncogene activities is through proviral insertional mutagenesis (see Oncogenes), which is driven by the strong promoter or enhancer activities of proviral long terminal repeat sequences. However, the latency for late transforming retrovirus-induced cancers can be protracted, as proviral insertion near a cellular oncogene tends to be random and require multiple rounds of cellular and viral replication before pathologic insertion can be achieved.More relevant to the development of cancer in human beings are DNA viruses, which include Epstein–Barr virus, human herpesvirus 8, and human papillomavirus (Martin & Gutkind, 2008). Mechanistically, once integrated into the host cell genome, a DNA virus can transcribe viral-specific proteins, which promote the immortalization of infected cells. Of the oncogenic DNA viruses, the molecular pathogenesis of human papillomavirus-associated cancers is understood with greater certainty in comparison with other DNA viral-induced malignancies. Human papillomavirus codes for two viral-specific proteins, E6 and E7, which serve to disable tumor suppressor protein activities, specifically p53 and Rb, respectively. The E6 viral protein accelerates the proteasome degradation of p53 protein, while the E7 protein competitively binds to Rb with consequent release of E2F family transcription factors (Dyson et al., 1989; Scheffner et al., 1993). Biologic activities of both E6 and E7 proteins result in the dysregulation of cell cycle checkpoints, which consequently promotes unchecked cellular proliferation, genomic instability, and mutagenesis.