oncogenic virus Flashcards
basic principle of oncogenesis
oncogenesis is the development of cancer due to disruption of normal control on cell proliferation.
Causes include mutagens such as free radicals, ionization radiation, chemical carcinogens etc OOOOR virus of course
Upregulation of cell growth in cancer can be due to mutations in genes that encode for proteins that regulate cell division.
or an infection with a virus that bring new genes that alter the regulation cycle.
traditional view of cancer hallmarks
1) Self-sufficiency of growth signals: Normal cells require signals to specify when they should grow and divide. Cancer cells no longer require external signals to be stimulated to grow, often having on-off switches that are stuck in the on position.
2) Insensitivity to anti-growth signals: It’s not enough to be triggered to grow and divide, because the biological systems are balanced with brakes to inhibit excessive cell growth. Cancer cells have lost this function.
3) Evading apoptosis: Apoptosis is a biological self-destruct program that cells have. It’s a normal part of development that leads to things like the space between fingers and toes (cells there are programmed to die at a particular point in normal development), and it’s also built into other cells when the growth is careening out of control. This automated self-destruct mechanism is turned off in cancer cells.
4) Limitless replicative potential: Though self-sufficiency of growth systems, insensitivity to anti-growth signals, and elimination of the self-destruct program should theoretically be enough to produce ongoing cancer cell growth and division, most cells also automatically stop growing beyond a certain point. Cancer cells continue to grow without any inhibition.
5) Sustained angiogenesis: Cancer cells without a new blood supply can’t grow beyond about 1-3 mm without outpacing their blood supply. If that happens, they have no way to receive nutrients and eliminate waste necessary to survive. Cancer cells put out molecular signals that attract new blood vessels to the cancer from outside, providing a new mechanism for the support needed to grow. Several agents targeting these angiogenic signals, such as Avastin (bevacizumab) have been studied and proven to improve survival in several types of cancer.
6) Tissue invasion and metastasis: The definition of malignant vs. benign is based largely on the potential of a malignancy (cancer) to invade into surrounding tissues and spread to other parts of the body.
patient derived xenograph
take from biopsy of human and directly introduce it under the skin in mice. Buuuut not possible cause a tumor need a microenvironnement . The implant needs to be irriguated so it cannot survive.
emerging view of cancer difference
now we are starting to consider epigenomic, microRNA and protein function too.
hallmarks involve evasion of the immune reponse, deregulation of cellular energetics
Additionally, two consequential characteristics of neoplasia facilitate acquisition of both core and emerging hallmarks.
Genomic instability and thus mutability in cancer cells with genetic alterations that drive tumor progression.
Inflammation by innate immune cells designed to fight infections and heal wounds can instead result in their inadvertent support of multiple hallmark capabilities, thereby manifesting the now widely appreciated tumor-promoting consequences of inflammatory responses.
to understand cellular mechanism
→ devise strategies for new targeted treatments.
DNA methylation IN CANCER
genomic DNA in a normal cell. The region shown contains repeat-rich, hypermethylated pericentromeric heterochromatin and an actively transcribed tumour suppressor gene (TSG) associated with a hypomethylated CpG island (indicated in red).
In tumour cells, repeat-rich heterochromatin becomes hypomethylated and this contributes to genomic instability, a hallmark of tumour cells, through increased mitotic recombination events. De novo methylation of CpG islands also occurs in cancer cells and can result in the transcriptional silencing of growth-regulatory genes. These changes in methylation are early events in tumorigenesis.
HPV
More than 70 types of human papillomavirus (HPV) have been described. Some cause benign papillomas of the skin (warts). Other strains, particularly HPV-16 and HPV-18, are linked to genital and anal cancers. Those viruses are sexually transmitted. HPV-16 and HPV-18 are found in the majority of squamous-cell carcinomas of the uterine cervix. Genital warts with low malignant potential are associated with HPV-6 and HPV-11.
When transforming DNA viruses infect a cell, they integrate their DNA into the genome of the host. At that point the virus does not reproduce but only produces the proteins necessary to commandeer the DNA synthesis machinery of the host cell. Two of those viral genes, E6 and E7, can act as oncogenes. The proteins they encode bind to the protein products of two important tumour suppressor genes, p53 and RB, respectively, knocking those proteins out of action and allowing the cell to grow and divide.
The E6 and E7 proteins of HPV-16 and HPV-18 bind to the RB and p53 proteins very tightly; in contrast, the E6 and E7 proteins of HPV-6 and HPV-11 (the low-risk types) bind RB and p53 with low affinity. The differences in binding ability of those proteins correlate with their ability to activate cell growth, and they are consistent with the differences in malignant potential of those virus strains (HR ad LR).
you therefore get continuous stimulation for S phase entry and cell growth stimulation by E7 and p53 loss
slow acting retroviruses
they dont bring an oncogene with hem
they do however induce cancer after a long period of months or years.
an exemple is apian leucosis virus
the promoter insertion and enhancer insertion operate a variety of oncogenes
they basically promote oncogene by insertion
ongenic transforming retroviruses
they induce tumors within days as they carry an oncogene
they carry v-src that induce cell transformation in the presence of the normal c-src proton oncogene you basically get a dominant gain of function
an example of these is rous sarcoma virus
non transforming retrovirus
Nontransforming viruses can randomly insert their DNA into proto-oncogenes, disrupting the expression of proteins that regulate the cell cycle. The promoter of the provirus DNA can also cause over expression of regulatory genes. Retroviruses can cause diseases such as cancer and immunodeficiency.
classification of virus-host interaction
acute infection: increase of viral load, immune response and then the immune system clears up
sublicinical infection: its asymptomatic the immune response clears up the virus
persistent and chronic infection: there is constant replication of the virus
latent infection: virus hides in the body and gets reactivated when the immune system of the host is lowered
slowly progressive disease: such as VIH after an extended latent, it gets slowly progressive
PD-1
during prolonged antigenic stimulation, PD1 over expression realist in inhibition of T cell proliferation and cytotoxic activity, the T cell are exhausted.
exhausted T cells cannot produce INF gamma
this is great in cancer cells as they only induce a weak immunee response, they avoid elimination by the immune system, and they create conditions that are necessary for further development of carcinogenesis
PD1 and PDL1 inhibitor are capable of converting the exhausted cells into effector T cells
CTLA-4
T cell activation requires two signals: MHC and TCR and CD28 and CD80/CD86
however after this, CTLA4 gets displaced on the membrane which reduce the T cell activation
