Principles of Viral Oncogenesis - 62

What is a tumor (neoplasm)?

A tumor (neoplasm) is a swelling caused by abnormal growth of cells.

What are the characteristics of benign tumors?

• Generally, benign tumors do not cause harm.

• They stay in the primary location with distinct, smooth, regular borders.

What are the characteristics of malignant tumors?

• Malignant tumors damage and impair the normal functions of tissues.

• They invade surrounding tissues and can metastasize.

What is oncogenesis?

Oncogenesis refers to the mechanisms involved in the development of cancer.

What is carcinogenesis?

Carcinogenesis is a complex, multistage process by which cancer develops.

What is a neoplasm?

A neoplasm is an abnormal new growth of cells.

What is hepatocellular carcinoma?

Hepatocellular carcinoma is a cancer of liver epithelial cells.

What is leukemia?

: Leukemia is a cancer of white blood cells

What does oncogenic mean?

Oncogenic means causing a tumor.

What is retinoblastoma?

Retinoblastoma is a cancer of the retina.

What is sarcoma?

Sarcoma is a cancer of fibroblasts.

What are the most common cancers in males?

• Lung and bronchus cancer

• Prostate cancer

• Colorectal cancer

What are the most common cancers in females?

• Lung and bronchus cancer

• Breast cancer

• Colorectal cancer

What are the characteristics of malignant tumors?

• Proliferate rapidly

• Diminished growth control

• Increased genetic mutations

• Loss of contact inhibition

• Invade local tissues (metastasize)

• Self-sufficient (do not need growth signals)

• Stimulate local angiogenesis

• Evade apoptosis (cell death)

What are the characteristics of benign tumors?

• Diminished growth control

• Do not invade other tissues

How do non-acute transforming retroviruses transform cells?

Non-acute transforming retroviruses transform cells via insertion and activation of proto-oncogenes (e.g., Murine leukemia virus).

: What is the mechanism of transformation by acute transforming retroviruses?

: What is the mechanism of transformation by acute transforming retroviruses?

What are trans-acting retroviruses?

Trans-acting retroviruses, such as Human T-cell Leukemia Virus (HTLV), can also cause cellular transformation.

What are the characteristics of non-acute transforming retroviruses?

• Common in nature

• No human cancers

• Incubation period is years

• Virus is replication competent

• Insert and disrupt gene regulation

How do non-acute transforming retroviruses transform cells?

• Provirus integrates at many sites in the genome

• Persists for the lifetime of the cell

• LTR (Long Terminal Repeats) contains promoter/enhancer elements

• Cellular regulatory proteins can bind to the LTR

: How does promoter insertion contribute to the transformation mechanism of non-acute retroviruses?

• Promoter insertion up-regulates cellular genes

• If insertion is 5’ of a gene (close), it activates gene expression

• Enhancer activation: LTR enhances transcription in neighboring genes

• This mechanism is more common

What are the characteristics of acute transforming retroviruses?

• Uncommon in nature

• No human cancers

• Incubation period is weeks

• Defective virus (requires helper virus)

• Carry viral oncogene (e.g., Avian sarcoma virus, MSV, FeSV)

How do acute transforming retroviruses transform cells?

• Presence of viral oncogenes can lead to a defective virus

• The defective virus requires a helper virus for replication

What are common oncogenes in acute transforming retroviruses?

• C-gene (c-myc): Cellular “proto-oncogene” involved in regulation or signaling

• V-gene (v-myc): Viral oncogene that affects cell regulation, leading to transformation

How does the V-oncogene contribute to the transformation mechanism of acute retroviruses?

• V-oncogene is under transcription control of the LTR

• Very high expression of the v-oncogene

• Tumors develop in weeks after infection

• Results in polyclonal tumors

What are the characteristics of trans-activating tumor viruses?

• Uncommon in nature

• Incubation period is years

• Action of viral regulatory proteins on cellular genes

• Virus is replication competent

• Examples: HTLV-1, BLV

What are the characteristics of HTLV-1 infection?

• Infects CD4+ lymphocytes

• Transforms a subset of lymphocytes

• Long incubation period

• Leads to numerous immortalized T-cells

• Acute adult T-cell leukemia/lymphoma (ATLL) occurs when an aggressive clone is generated

• Originally described in Japan in 1977

• Transmitted and acquired like HIV

How is HTLV-1 treated and what measures are used to prevent its transmission?

• Treatment: A combination of AZT and interferon (IFN)-α has been effective in some patients with acute adult T-cell leukemia/lymphoma (ATLL). However, no specific treatment has been approved for HTLV-1 infection.

• Prevention and Control:

  • Sexual precautions

  • Screening of the blood supply

  • Increased awareness of potential risks and diseases

  • Routine screening for HTLV-1, HIV, hepatitis B, and hepatitis C to protect the blood supply

  • Maternal infection of children is difficult to control

What is the difference between leukemia and lymphoma?

• Leukemia: Affects the blood and bone marrow. It leads to the production of abnormal white blood cells, which circulate in the bloodstream.

• Lymphoma: Primarily affects the lymph nodes, though it can spread to other parts of the body. It involves the abnormal growth of lymphocytes (a type of white blood cell).

: How does HTLV-1 transform cells?

HTLV-1 carries the accessory gene tax, which acts as a transcriptional regulator. Tax activates promoters in the viral LTR (long terminal repeat) and also cellular genes, leading to the transformation of infected cells.

: What role does the tax gene play in the transformation of cells by HTLV-1?

The tax gene activates several cellular genes, including the auto-stimulating IL-2 loop, which leads to uncontrolled T-cell proliferation and contributes to cell transformation.

What are the characteristics of Hepatitis C Virus (HCV) and its role in liver cancer?

• Hepatitis C Virus (HCV) is a member of the Flaviviridae family with a (+) ssRNA genome.

• HCV doesn’t grow in cell culture.

• It predisposes patients to primary hepatocellular carcinoma (PHC).

What is the mechanism of HCV transformation?

HCV persistently infects hepatocytes​, causes continual destruction and regeneration of liver tissue​, and continual induction of cell growth may lead to cancer​.

: Which DNA viruses are involved in oncogenesis?

Adeno, Papilloma, Polyoma, Hepadna, Herpes.

Which viruses are associated with cancer in humans?

HPV (Cervical cancer), MCC (Merkel cell carcinoma), HepB (Primary hepatocellular carcinoma), EBV (B cell lymphomas), HHV-8 (Kaposi Sarcoma).

Which viruses are associated with cancer in animals?

SV40 (Cancer in animals), Myxoma (Cancer in animals).

How do most DNA viruses contribute to cancer?

: DNA viruses can push cells into S phase by upregulating activating genes and blocking tumor suppressor genes.

4o mini

What are the mechanisms of transformation by small DNA viruses?

• Induce S phase genes

• Extend life of cell

• Block action of normal regulatory proteins

• Often tumor suppressor genes

• E.g., papillomaviruses

What are the mechanisms of transformation by large DNA viruses?

• Interact with extracellular growth factors or intracellular signaling systems

• Results in perpetual cellular replication

• Encoding homologs of cellular genes involved in signaling

• E.g., herpesviruses EBV and HHV-8

What are the characteristics of tumor suppressor genes?

• Negative regulators of cell growth

• Often deleted or damaged in cancer cells

• e.g., p53

• Regulates G1 → S

• 50% of human tumors have p53 gene inactivated

: What are the key features of Human Papillomavirus (HPV)?

• 100 types

• Cause benign epithelial overgrowths - warts

• Can cause cervical carcinoma

• Types 16, 18, 31

• Two viral proteins E6, E7

• Maintain cells in S phase for virus replication

• Involved in cell immortalization and transformation

What are the key features of human polyomaviruses and Merkel cell carcinoma?

• Human Polyomaviruses SV40

• T antigen

• No human cancers

• Merkel Cell Carcinoma

• Merkel cell polyomavirus

• Rare, aggressive skin cancer

• Sun exposure

• Weakened immune system

What are the key features of Epstein-Barr Virus (a γ-Herpesvirus)?

• Infects cells bearing CD21

• B-lymphocytes + a few epithelial cells

• Co-factor in carcinogenesis

• Nasal pharyngeal carcinoma

• Burkitt’s lymphoma

• Hodgkin’s Disease

What are the key features of Kaposi Sarcoma?

• Neoplasm of the skin and viscera

• Older men in Eastern Europe and Mediterranean, African children

• From 1980’s on greatest incidence was in homosexual male AIDS patients

• 10,000× general population

• Etiological agent identified as HHV-8

What are the key features of Hepatitis B Virus (HBV)?

• Hepadnaviridae

• Persistent infection of the liver

• Long incubation before cancer develops

• Chronic HBV infection and increased proliferation of hepatocytes

• Fragments of integrated HBV DNA are found in cancer cells

• Multifactorial disease