As the acquisition of a proto-oncogene from the

            As was previously mentioned, early studies of retroviral – induction of tumors has helped shape oncology (116). The discovery of RSV led to the detection of the first proto-oncogene which was later found to originate from host cells (116). This led to an understanding of molecular mechanisms in all cancers with and without a retroviral origin by studying how proto-oncogenes cause cancer (116). Retroviruses also provide a model system to study retroviral carcinogenesis, especially in a murine model system, through induction of transformed cells in vitro and implantation into immunocompromised or syntenic rodents (116). Through the detection of proto-oncogenes which are often involved in cell cycle regulation and growth, retroviral carcinogenesis has led to a greater understanding in normal cellular mechanisms and growth pathways (116).

Also mentioned earlier in this chapter was the connection of retroviruses to cancer. This was first established with Ellerman, Bang, and Rous’ discoveries of ASLV, isolated from avian sarcomas and leukosis (1, 116). Retroviruses isolated from other mammalian cancers such as murine, cervide, equine, feline, and – eventually – primate were isolated between the 1950s and 1980s. Oncogenic retroviruses in these species are not all from one clade or exogenous. Some are betaretroviruses (MMTV, JSRV) while others are alpharetroviruses (ASLV), gammaretrovirsues (MLV), and lentiviruses (HTLV). MLVs and FeLVs exist in both endogenous and exogenous forms and are capable of inducing leukemia (116). JSRV and MMTV also exist in exogenous and endogenous forms, but enJSRV is protective of the host against its exogenous cancer-causing counterpart while MMTV can cause mammary carcinoma in both its endogenous and exogenous form (116).

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Retroviruses
such as RSV can cause cancer in host cells through the acquisition of a
proto-oncogene from the cell or through proviral insertion adjacent or within a
proto-oncogene or tumor suppressor (116). In this respect, the replication
pathway of a retrovirus has the potential to be oncogenic. Retroviruses can
acquire proto-oncogenes through recombination with the host. In most cases,
this destroys the replication potential for this virus in that it will
effectively swap portions of its own genome for the proto-oncogene (116). This
can involve the removal of all ORFs, some of them, or a small fraction of one. To
continue replicating, this virus will need another replication competent virus
that will provide the necessary core and enzymatic proteins for transportation
to a new host. This virus is known as a “helper” virus, and has been reported
with ALV strains such as AMV, E26-AMV, and AEV-ES4 (116, Figure 1.6.3). It
should also be mentioned that of the ALV strains RSV is a special case: this
virus has been shown to acquire the proto-oncogene src without compromising its replicative capacity (116, Figure
1.6.3).

In
terms of their carcinogenic potential, both the helper and proto-oncogene –
containing (also known as “transforming”) provirus can transform cells.
Considering that the transforming provirus contains a proto-oncogene, this
virus upon infection of a host will drive expression of their proto-oncogene to
induce transformation. This typically has a quick onset in in vitro and in vivo
models (116). The helper virus has a longer latency period and transforms cells
through proviral insertion upstream of a proto-oncogene or within a tumor
suppressor (116, Figure 1.6.1, Figure 1.6.2). This method results in a longer
incubation period in that a provirus must insert into the “right” site. A
retrovirus that insert upstream of proto-oncogenes could activate their
expression through their 5′ LTR either directly upstream or from within an
intron. In either situation, it will lead to overexpression of the
proto-oncogene within the host, yet insertion within an intron will lead to an
altered form that is missing one or more exons. Expression of a proto-oncogene
through a provirus’ 5′ LTR could also lead to alternate splicing into a
hyperactive or inactive product. It is also possible that a retrovirus
integrated antisense to a proto-oncogene could allow for enhancer binding to
their LTR, allowing for increased expression of the proto-oncogene.

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