19: Cancer and the immune system Flashcards
What is the difference between a benign and a malignant tumor?
Benign:
Tumor that is not capable of indefinite growth and does not invade the healthy surrounding tissue.
Malignant:
- A tumor that continues to grow and becomes progressively more invasive => cancer.
- Exhibit metastasis or spread.
Name some classifications of cancers
Carcinoma (80-90%):
- Epithelial origin
- Skin, breast, prostate, lung…
Sarcoma (1%):
- Mesodermal connective tissues (bone, fat, cartilage) or in cells derived from hematopoietic stem cells (HSCs).
From blood cells (9%):
- Lymphoma, myeloma, leukemia
Name some risk factors of cancer
- Tobacco
- Diet, obesity
- Infections
- Hormones
- Ionizing radiation
- Alcohol
- Genetics (heritage)
- Environmental pollution
=> Cells accumulate genetic errors and multiply without control.
What are the hallmarks of cancer?
Cancer cells can:
- Stimulate their own growth
- Ignore growth-inhibitory signals
- Avoid death by apoptosis
- Develop blood supply (angiogenesis)
- Leave their site of origin to invade other tissues
- Replicate constantly to expand their numbers
- Evade and outrun the immune response-
Have been acquired via genetic mutations.
What is an oncogene, and how is it formed?
Proto-oncogene: normal cellular gene involved in growth and proliferation.
Mutated form: oncogene - Gain of function => cancer - Encodes proteins that regulate cell growth or programmed cell death: • Growth factors and receptors • Signal transducers • Transcription factors • Anti-apoptotic factors
Proto-oncogene -> oncogene:
- Mutation: increase in activity and/or loss of regulation
- Increase in protein concentration: Increased expression and/or stability. Gene duplication/amplification => more protein.
- Chromosomal translocation: Increased expression in wrong cell type or at wrong times. Expression of constitutive active hybrid protein.
What is a tumor-suppressor gene (anti-oncogene) and how can it cause cancer?
Encode proteins that inhibit cell proliferation.
Loss of function => cancer
Caused by:
- Mutations
• p53 (>50% of cancers)
- Chromosomal aberrations (deletions/aneuploidy)
• Deletion of chromosome 13 band q14.1 associated with retinoblastoma (Rb)
- Increased degradation
• an HPV gene, E6, interacts with the p53 gene, causing the degradation of the p53 protein, thus allowing the cell cycle to go unchecked
What is an apoptosis gene and how can it cause cancer?
Control programmed cell death.
Pro-apoptotic genes act like tumor suppressors, normally inhibiting cell survival.
Anti-apoptotic genes behave more like oncogenes, promoting cell survival.
What are the four main steps of malignant transformation?
Initiation:
- Initiating mutation
Clonal expansion => promotion:
- Accumulation of tumor cells. Localized benign tumor.
Second clonal expansion => progression:
- Invasive tumor cells
- Malignant
Multiple parallel clonal expansions =>
metastasis:
- Generation of small clusters of cancer cells that dislodge from the tumor and are carried by the blood or lymph to other sites in the body.
What are the the two (four) groups of tumor antigenes?
Tumor-specific Ag (TSA):
- Encoded by genes exclusively expressed by tumors.
- Encoded by variant forms of normal genes that are altered by mutations.
Tumor-associated Ag (TAA):
- Normally expressed only at certain stages of development.
- Overexpressed in particular tumors.
What is a tumor-specific antigen (TSA)?
Nonself proteins that arise from DNA mutation or cancer-causing viruses, wielding peptides recognized by the immune system as foreign.
Unique to tumor-cells.
Hard to detect:
- Tumor cells expressing moderate/high levels of the antigen are eliminated
by the immune response
- Cells bearing low levels of the antigen survives
Can be identified by:
- Chemical carcinogens
- Physical carcinogens (UV-light)
- Virus (eg HPV)
What is a tumor-associated antigen (TAA)?
Also found on normal cells but:
- Normally expressed at extremely low levels (overexpressed in tumor cells): GFs, GF receptors…
- Normally expressed only during fetal development (when the immune system is immature)
- Stress related proteins
Can be recognized by the immune system, or used clinically to monitor or therapeutically target the cancer.
By which three mechanisms does the immune system control or inhibit cancer?
- By destroying viruses that are known to transform cells.
- By rapidly eliminating pathogens and regulating inflammation.
- By actively identifying and eliminating transformed cells (immunosurveillance)
What is cancer immunoediting?
Process where the interaction of tumor cells with the immune system generates tumor variants with altered
immunogenicity.
Three phases:
- Elimination (immune surveillance, the tumor is eliminated)
- Equilibrium (tumor dormancy)
- Escape (growing tumor)
What are the innate inhibitors of cancer?
NK cells:
- Balance of activating and inhibiting signals.
• “Missing self” by downregulation of MHC complexes.
• “Altered” / “induced” self by changes in protein expression, DAMPs etc.
- Use cytolytic granules with e.g., perforin to kill target tumor cells.
- Secrete IFN-γ, anticancer cytokine that encourages MHC expression in DCs => stimulation of CTLs.
Macrophages:
- E.g. proinflammatory M1 type
- Like NK: have Fc receptors that can bind to tumor Ag => antigen-dependent cell-mediated cytotoxicity (ADCC).
- Secrete TNF-α with potent anti-tumor activity.
Eosinophils:
- Secrete IL-5 => stimulates B cell growth and Ig(A) secretion. Mediator in eosinophil activation.
What are the adaptive cellular processes and the cells involved in cancer eradication?
Antitumor CTLs are the (adaptive) cell type most associated with cancer eradication.
Activated DCs and T(H)1 type cells also assist.
B cells create anti-tumor Ab’s as a response to tumor-specific Ag’s.
=> allows cells with Fc receptors, such as NK cells and macrophages, to induce ADCC in tumor targets.
