ORGB 423 Lecture Notes - Lecture 17: Merkel-Cell Carcinoma, Cervical Intraepithelial Neoplasia, Denis Parsons Burkitt
12 Jun 2018
School
Department
Course
Professor
MIMM466 Viral Pathogenesis
2018-02-05 LEC 17,18 Viruses and Hematology: a Gateway to Cancer
Jean-Pierre Routy
We need balance between tolerance and Immunity
• We live with a large quantity of non-human cells that we need to tolerate, while avoiding invasive pathogens
• Factors associated with loss of balance: age, genetics, microbiome, viral infection (topic of this talk),
exposure to sunlight (has to do with skin cancer)
o E.g. microbiome: new immune-therapies for cancer (e.g. anti-PD1), will not work if the patient is
taking antibiotics, will result in toxicity
History of viruses and Cancer
• 1909: Ellerman and Bang in Copenhagen transmitted leukemia in chicken through cell-free, filtered extract,
suggesting infectious etiology (i.e. must be some soluble factor)
• 1911: Rous, USA transmission of chicken sarcoma by use of filtrates
• 1973: SV40 can induce leukemia in certain experimental conditions
• Oncogenic viruses can promote malignancies in several animals
Viruses associated with Cancer
Merkel cell
polyomavirus
(MCV)
• Causes rare neuro-endocrine cancer (skin cancer)
• Discovered in 2008 in samples from a Merkel cell carcinoma skin cancer
o Can be found in skin and saliva
• DNA virus that affects the host DNA leading to Merkel cell cancer
• All MCV are linked to Merkel cell cancer (i.e. Merkel cell cancer = MCV infection)
• Treatment: surgery and anti-PD-L1 therapy
o Blocking the inhibitor allows the immune system to fight the virus
EBV
(Epstein-Barr
virus)
• 1952: Denis Burkitt described a childhood lymphoma in Uganda
o Linked with malaria in endemic zones: malaria modifies the immune system to
be weaker, allowing the virus to better establish in your body
• 1965: Epstein and Barr discovered herpes virus particles (EBV or HHV-4) in Burkitt’s
lymphoma via EM
o First human virus associated with cancer
• EBV associated with nasopharyngeal carcinoma, gastric carcinoma, HL, B/T-cell
lymphoma in immunosuppressed patients
o EBV is not sufficient for cancer; require other factors (including genetics,
immunity, immunosuppression, environmental factors…etc.)
• EBV immortalizes B cells by inhibiting death mechanisms
• 90% of adults worldwide are seropositive for EBV
Human
Papillomavirus
(HPV)
• 200 genetically different strains of related viruses causing papillomas or warts
• >26% of women in the US are infected
• Some types of HPV only grow in skin, while others grow in mucous membranes (e.g.
mouth, throat, anus, vagina)
• Strains 16, 18: cause 70% of cervical cancers
• Strains 6, 10: cause genital warts
• Spread by contact with infected areas (e.g. via sex), controlled by vaccination
• 20-45% of asymptomatic infections can be cleared by the immune system
o Younger = ! chance of clearing the virus
o HPV can be cleared within 1-2 years of exposure
• HPV can persist and develop cervical intraepithelial neoplasia (CIN)
• Takes years to progress from dysplasia (cell abnormality) to cancer
o Co-factors of progression: smoking, HIV co-infection, immunosuppression
HCV
• 170M infected worldwide, mostly in Africa, South America and South-East Asia
o Incidence is dependent on intravenous drug use
• Transmission: blood contact, sex
• Virus does not integrate into host genome, so if you treat the infection early, you can
essentially cure it (preventable)
• Causes severe liver inflammation, cirrhosis, and cancer (i.e. hepatoma) if chronic
• No vaccine, but treatable with pills
o Can never fully cure because viral DNA integrates into genome
• No direct oncogenic effect of the virus: doesn’t directly cause the cancer, but
combination of chronic inflammation and tissue damage creates an environment that
leads to cancer
• Research progress:
o 1996: associated with B cell lymphoma and cryoglobulimemia (protein that
clots at low temperatures and causes necrosis in extremities)
o 2002: IFN and ribavirine therapy causes remission of marginal-zone lymphoma
o 2012: immune activation, insulin resistance, cholesterol metabolism
o 2013: cure without IFN therapy, with risk of persistent hepatocellular carcinoma
HBV
• Endemic worldwide, but highest in Africa and Asia
• 400M infected worldwide
• Transmitted via contaminated blood, sweat, tears, sexual contact, vertical
transmission (motheràchild)
• Chronic infection to leads to liver cirrhosis and hepatocellular carcinoma (HCC)
o Vaccination can prevent HCC
o Less carcinogenic than HCV (can cause cancer without cirrhosis)
• HBV encodes HBX that can promote cell proliferation and interfere with DNA repair
• Causes chronic inflammation and tissue regeneration
HTLV-1
• Receptor: IL2 receptor
• History
o 1976: distribution and clinical presentation (leukemia, lymphoma, myelopathy)
described by Tatatsuki
o 1980s: Poesz identified first retrovirus to cause human disease, shown to
transmit like HIV
o 2003: viral proliferation and immune control
o 2012: viral load and leukemia development
• RARELY causes leukemia with high fatality, can even rebound after remission
o Requires immediate allogenic stem cell transplant
• Works by immortalizing the Tax protein
• Most prevalent in Japan and Africa, and causes different diseases in different
geographical areas
HIV
• First reported Kaposa Sarcoma (KS) in 1981, in gay men
• AIDS defining cancers: KS, non-hodgkin lymphoma, cervical cancer (HPV)
o HPV is the main cause of cervical cancer, but it was associated with AIDS early
on due to epidemiological frequency
• Non-AIDS defining cancers: some types of tumors were found in greater frequency in
HIV infected patients
Kaposi Sarcoma
• Classical: lesions mostly in lower extremities, found in middle aged men
o Kaposi discovered skin lesion which was found frequently in gay men, more frequent if you live near
a volcano (acidity in the ground)
o Immunosuppression is an important factor
Document Summary
2018-02-05 lec 17,18 viruses and hematology: a gateway to cancer. Merkel cell polyomavirus (mcv: causes rare neuro-endocrine cancer (skin cancer, discovered in 2008 in samples from a merkel cell carcinoma skin cancer. Htlv-1: 170m infected worldwide, mostly in africa, south america and south-east asia. Requires immediate allogenic stem cell transplant: works by immortalizing the tax protein, most prevalent in japan and africa, and causes different diseases in different geographical areas. Infection related cancers occur more frequently in hiv+ patients and transplant recipients than the general population: true for cancer related to ebv, hhv-8, hbv, hcv, hpv, e. g. Kaposi sarcoma had much higher incidence in hiv+ and transplant recipients. Level of immunosuppression and cancer risk: the immune system strength is measured by cd4 cell count: immune system = sickness, non-hodgekins lymphoma, burkitt must treat early, occurs when immune system is still relatively present (cd4:350-500)
