Chapter 17- Cancer Flashcards
Cancer
Uncontrolled growth of abnormal cells in the body. There are 10^14 cells in the body; so the chance of an individual cell becoming cancerous is 3x10^-14. Cancer can develop in almost any organ or tissue- there are more than 100 types of cancer. Cancer has caused about 20% of deaths in industrialized nations. Rates are rising as more people live to an old age
3 most common cancers in men
Prostate, lung, and colon
3 most common cancers in women
Breast, colon, and lung
Cancer risk factors (8)
- Carcinogens (asbestos)
- Behavior (alcohol use, smoking)
- Hormones (HRT)
- Psychological stress
- Heredity
- Radiation and UV light
- Physical inactivity/obesity
- Viral infections-10-20% of cancers worldwide
Carcinomas
Cancer of the epithelial cells (GI tract, urogenital tract)
Sarcomas
Cancers of other cell types
Leukemias
Cancers derived from immune cells
Lymphomas
Cancer involving lymphocytes and lymphoid tissues
Myelomas
Cancer involving the bone marrow
Cancer and gene mutations
Cancer arises from gene mutations. The cell becomes cancerous by accumulating multiple mutations
Proto-oncogene
Cellular genes that
promote normal growth and cell division, like transcription factors, signal transduction molecules, and cell-cycle regulators
Cellular oncogene
A mutated form of
proto-oncogene that causes tumor formation
Viral oncogene
Viral gene responsible for oncogenicity of the virus
Cell cycle phases
Interphase (G1, S, G2), as well as the mitotic phase (mitosis and cytokinesis
Cell cycle
The process through which cells replicate and make 2 new cells. It contains checkpoints to monitor and regulate the cycle cycle, between G1/S and G2/M. Dysregulation of cell cycle components or regulatory molecules may lead to tumor formation
Cell cycle regulatory molecules
Cyclins & cyclin-dependent kinases (CDKs) control DNA replication and initiation of mitosis
Tumor suppression genes
Encode proteins that inhibit the conversion of a normal cell into a cancer cell
p53
A tumor suppressor gene that is activated in response to DNA damage. It arrests the cell cycle until damage is repaired and can induce apoptosis if necessary. More than 50% of human cancers have p53 mutations or mutations in other genes
interfering with p53 function
Tumorigenesis
Cancers develop in progressive steps beginning with mildly
aberrant cells and progressing to cells that are increasingly
tumorigenic and malignant- a single mutation is not sufficient to transform a normal cell. Each step appears to be the result of two or more genetic alterations that progressively release the cell from the normal controls on cell proliferation and malignancy. Another indication that cancer is a multistep process is the delay that occurs between exposure to carcinogens and the appearance of the cancer- cigarette smoking, asbestos exposure
Cancer stem cell hypothesis
Tumor cells that proliferate give rise to cancer stem cells that have the capacity for self-renewal and the ability to generate heterogeneous lineages of cancer cells. The stem cell divides unevenly, creating one daughter cell that becomes a mature cell type
and one that remains a stem cell. Every tumor cell has the potential to form a new tumor.
Cancer cellular transformation (5)
A change in the morphological, biochemical, or growth properties of a cell.
1. Cells divide uncontrollably, which circumvent the need for growth signals
2. Metabolic changes- the cells grow rapidly
3. Increased levels of enzymes important for nucleic acid synthesis
4. Cells bypass apoptosis
5. Avoid host immunosurveillance
Benign tumors
Result from unregulated cell
growth forming a multicellular mass (limited in size) that can be removed by surgery, causing no
serious harm. Warts are an example
Malignant tumors
Continually grow in size and
can invade adjacent tissues; are difficult to treat and may become life threatening
Metastasis
Tumor cells that break loose from the primary tumor and form secondary tumors (metastases)
How does metastasis occur?
Cancer cells acquire the ability to disengage from the original tumor site, enter the blood or lymphatic system, and invade surrounding tissues. They exhibit reduced expression of genes controlling cell
adhesion. There is also digestion of the extracellular matrix and basal lamina via increased expression of proteolytic enzymes
Mutagen
A substance or event that damages DNA and causes mutations
Carcinogenesis
A mutagen that increases the risk of cancer. A mutation can occur in proto-oncogenes or tumor suppressor genes, which can result in abnormal replication of the cell cycle or disruption of controls over apoptosis or metastasis
Examples of carcinogens
Tobacco smoke is the most significant environmental carcinogen. It contains more than 60 mutagenic chemicals and is responsible for 30% of human cancer deaths. Natural radiation (UV light, X rays), natural dietary substances, and substances in the external
environment can cause DNA lesions
Viruses and cancer
Around 15% of human cancers are associated with viruses, which is the second greatest risk of cancer next to tobacco smoke. Retroviruses and DNA viruses both contribute to cancer risk
Retroviruses
RNA viruses that are converted into DNA by the reverse transcriptase enzyme- contribute to the development of cancer by integrating into the host genome
DNA viruses
Contribute to cancer by expressing proteins that stimulate cell cycle progression. Can cause lifelong latent infections
Retrovirus life cycle
The DNA copy of the viral genome enters the host cell and integrates at random, forming what is called a provirus. The provirus is then replicated along with the rest of the host DNA. A retrovirus may not kill a cell but may continue to use it as a factory to replicate more viruses that will then infect surrounding cells.
3 ways that retroviruses may cause cancer
- Proviral DNA may integrate near one of the normal
proto-oncogenes and stimulate high levels or inappropriate timing of transcription of the proto-oncogenes. - Proviral DNA may inactivate a tumor suppressor gene
- Expression of viral oncogene (v-onc) may lead to
inappropriate cell growth or to abnormal expression of cancer-related cellular genes
DNA viruses and cancer
DNA tumor viruses differ from RNA tumor viruses in their structure, genome organization, and replication strategies. The oncogenes of DNA tumor viruses are essential viral genes that are used in replication, and mostly target tumor suppressor genes
Epstein-Barr virus
A DNA virus that is also called human herpes virus 4. It causes infectious mononucleosis. EBV persistently infects B lymphocytes and is associated with Burkitt’s lymphoma (BL). The DNA of BL tumors contain genetic aberrations
Who gets Burkitt’s lymphoma?
90% of the world’s population is seropositive for EBV, but BL is relatively rare. It is most common in children in central Africa, accounting for 30-60% of malignant tumors. This is because children in this region tend to suffer from conditions that weaken their immune system, like chronic malaria or AIDS
Kaposi’s sarcoma associated herpesvirus
Also referred to as human herpesvirus 8. It causes a rare skin cancer called Kaposi’s sarcoma. The viral genome encodes a cyclin and a Bcl2 homolog, which causes a loss of cell cycle control and blocks apoptosis
Which groups most commonly get Kaposi’s sarcoma?
- Elderly men of Mediterranean, Middle Eastern, or Eastern European descent
- AIDS patients (50% risk)
Hepatitis B virus
Causes chronic hepatitis that can progress to cirrhosis and liver cancer (HCC). HBV infects the hepatocytes of the liver, and HCC tumors in HBV patients usually contain viral DNA. The virus is transmitted by infected blood or body fluids. The HBV vaccine was the first vaccine to prevent a cancer
Hepatitis C virus
Called the “silent epidemic” as many infected people show few or no signs of disease for years, even decades. 55-85% of infected people experience a chronic infection, which results in a chronic liver disease. The virus spreads almost exclusively through blood contact. Complications of HCV account for 30% of all liver transplants
How is HCV diagnosed?
An anti-HCV antibody test, followed by a PCR test
Risk factors for HCV
75% of patients in the United States living with HCV infection were born between 1945
and 1965. Risk factors include past/present drug use, sex with IV drug user, or blood transfusion before 1992
Human papillomavirus (HPV)
Infections are most common among sexually active adults and teenagers. It is the most prevalent sexually transmitted disease in the world. There is a 4-20 year latent period between infection and cancer
Categories of HPV
- Low-risk types are benign and cause warts or papillomas
(e.g., genital warts, warts on hands and soles of feet). - High-risk types cause cervical, vulva, vagina, anus, and
penis cancers (e.g., types 16 and 18)
HPV and oncogenesis
HPV DNA is found in nearly all cervical cancers. The HPV genome is integrated into host cells, where it inactivates tumor suppressor genes p53 and retinoblastoma protein
HPV vaccination
The vaccine is recommended for both girls and boys ages 11-12. It is a 2-3 shot series which prevents 70% of cancers. Recommended for both genders because HPV can be found in semen, and high-risk HPV types are responsible for a large proportion of cancers of the mouth and pharynx in males
HPV vaccines (3)
- Gardasil (2006)- protects against HPV 6, 11, 16, and 18
- Cervarix (2009)- protects against HPV 16 and 18
- Gardasil-9 (2015)- protects against the original 4 strains, as well as 31, 33, 45, 52, and 58. It is the only HPV vaccine available in the US as of 2017. As of 2018, the FDA approved its use for people 27-45 years old
Cancer immunosurveillance
The immune system surveys for cancer cells and eliminates them. Most cancer cells are eliminated at an early stage. Early studies have demonstrated a role for MHC molecules and cytotoxic T cells in this process. Tumor rejection antigens come from tumors and are presented to T cells by MHC molecules
Elimination phase of cancer immunosurveillance
When the immune system recognizes and destroys potential tumor cells
Innate immune system cancer immunosurveillance
- NK cells: perforin-mediated killing
- Gamma delta T cells: recognize stress proteins and
glycolipids widely expressed by many tumors; cytotoxic activity & produce IFN-γ - IFN-γ leads to increased MHC
Adaptive immune system cancer immunosurveillance
- CD8 T cells- cytotoxicity
- CD4 T cells- help prime CD8 T cells, cytokine secretion, and help B cells
Tumor specific antigens
Antigens that are present on tumor cells alone. They can be derived from viral proteins, mutated cellular proteins, or tumor-specific recombined proteins. Tumor-specific antigens also include novel protein antigens produced by the fusion of cellular genes, like BCR and ABL
Tumor associated antigens
Antigens that are expressed on both normal and tumor cells, but at differing amounts. They are derived from normal cellular proteins that the body has not been exposed to or not made tolerant to. Not normally produced in high amounts
Tumor antigens
Transformed/cancerous cells have genomic differences and therefore can express different antigens. Tumor antigens can be tumor specific or tumor associated. Some studies have demonstrated a role for MHC molecules in presenting tumor rejection antigens to CD8 T cells so the cancer cells can be eliminated
How do tumor-specific antigens arise?
They may have been modified from a point mutation or from abnormal protein modification (glycosylation, phosphorylation). Peptide splicing, where peptides from self proteins are cut and pasted, can generate antigens that are recognized as “non-self” by CD8 T cells
Where are tumor-associated antigens found?
Usually found in immune privileged sites. Many tumor-associated antigens are normally
expressed by the testes or on embryonic cells- these tissues do not express polymorphic HLA class I or class II. CT antigens (cancer/testis antigens) are antigens found in these areas
Cancer immunoediting
Cancer cells are genetically unstable and can escape elimination by producing altered antigens. Through mutations, variant tumor cells eventually arise that are resistant to being killed, and new varieties of tumors can develop to spread unchallenged
Immune evasion by tumors
Cancers that survive the elimination phase undergo mutations to aid in their survival, with cancer immunoediting being one example. The tumors then either enter the prolonged period of dormancy or into the escape phase, where they develop their mechanisms of evasion
How does immune evasion occur (4)
- Tumor cells increase expression of MIC, a stress protein expressed by epithelial tumors
- NKG2D, which is expressed on NK cells and γ:δ T cells, binds to MIC and allows the cells to kill the tumor
- However, variant tumor cells express a protease that cleaves MIC. They then shed soluble MIC, which binds to the lymphocyte NKGD and induces degradation of the immune complex
- The tumor escapes killing- variant tumor cells survive and proliferate
Mechanisms by which tumors avoid immune recognition (5)
- Low immunogenicity- they have a lack of co-stimulatory molecules
- Tumor treated as a self antigen- the tumor antigens are presented by APCs in absence of co-stimulation tolerize T cells
- Antigenic modulation- antibodies against tumor cell-surface antigens can induce endocytosis and degradation of the antigen. The immune system selects for antigen-loss variants
- The tumor creates a suppressive microenvironment
- Tumor induced privileged site- the tumor creates a physical barrier, like collagen, that separates it from immune cells
Which changes occur to create an immunosuppressive tumor microenvironment?
- Secretion of suppressive cytokines (TGF-β)
- Secretion of indoleamine 2,3-
dioxygenase (IDO) - Recruitment of myeloid-derived suppressor cells
TGF-β
Immunosuppressive cytokine which induces regulatory T cells and suppresses tumor-specific CD4 and CD8 T cells in the tumor immunosuppressive microenvironment
Indoleamine 2,3-
dioxygenase (IDO)
Immunosuppressive molecule, suppresses T cell effector functions
Myeloid-derived suppressor cells
Secrete IL-10 and reduce dendritic cell activity
Programmed cell death protein 1 (PD-1)
Found on effector T cells. It binds to PDL-1 and acts as an “off: which to negatively regulate TCR signaling
Programmed death ligand 1 (PD-L1)
The ligand for PD-1. Its expression on tumor cells inhibits anti-tumor activity through the engagement of PD-1 on effector T cells. Expression of PD-L1 on tumors is correlated
with reduced survival
Cancer treatment options (4)
- Surgery to remove the tumor
- Radiation therapy
- Chemotherapy
- Immunotherapy
Radiation therapy
Uses external beams or radioactive “seeds” to slow growth or kill cancer cells
Chemotherapy
One or more anti-cancer drugs may be used. Mechanisms include inhibiting DNA and RNA synthesis and interrupting cell division. Risks- depresses the immune system and causes myelosuppression
Immunotherapy
Helps the patient’s immune system to fight cancer. Can be used alone or in concert with other drugs
Why can’t vaccines be based off of tumor antigens?
This would be the ideal approach, but tumor rejection antigens can differ from patient to patient and may only be presented by certain MHC alleles. The best source of antigens for vaccines are individual patient tumors that are removed in surgery
Tumor-based vaccines
Utilizes irradiated tumors or extracts mixed with components to enhance the immunogenicity of the injected tumor. Bacillus Calmette-Guérin (BCG): induces a TH1 response which activates CD8 T cells, NK cells, and gd T cells to attack abnormal
cancer cells. Used to treat bladder cancer
Dendritic cell vaccines
DCs are attractive due to their ability to present antigens, cross-presentation, & expression of co-
stimulatory molecules. You could harvest DCs from patient or differentiate monocytes in vitro; but both are challenging. The cells are then cultured with tumor antigens, peptides derived from tumor antigens, or DNA encoding tumor
antigens. Then, inject into patients to stimulate tumor-specific T cells
Provenge
A dendritic cell vaccine used to treat prostate cancer. It uses matured DCs that are cultured with the prostate cancer antigen PAP (found in 95% of cancers). The death rate was reduced by 22% and there was a 4 month increase in survival time
Tumor infiltrating lymphocytes (TIL)
TIL (containing T cells) are isolated from a biopsy and expanded in vitro. The TILs are then cultured with IL-2 and autologous DCs expressing tumor antigens. The tumor-specific TILs are then infused into the patient, where they can go attack the tumor. Since these are the patient’s own cells, there is not risk of rejection
CAR T cells
Requires drawing blood from patients and separating out the T cells. A disarmed virus is used to genetically engineer the T cells to express chimeric antigen receptors that will recognize and attach to an antigen on tumor cells. CAR T cells are expanded in the laboratory and then infused into the patient. More effective in blood cancers
Chimeric receptor
Has an antigen binding site that is composed of VH and VL. The V domains are connected to a transmembrane protein containing 3 signaling domains. It sends a strong signal to the T cell to ensure that the cell is not rendered anergic. T cells that are not specific for the tumor can also be activated to attack the tumor
Anti-CD19 CAR T cells
Used to treat ALL. Cancer disappeared in 27/30 patients, and these patients have remained in remission. Side effects- cytokine release, killing of healthy B cells
CTLA-4
An immune checkpoint molecule. Acts as a negative regulator of T cell co-stimulation. It competes with CD28 for access to B7.
Ipilimumab
An anti-CTLA-4 antibody that is used to treat advanced melanoma. The antibody improves the 2 year survival rate to 24% (75% of patients survive less than 1 year)
PD-L1 and PD-L2
Ligands that are expressed on antigen presenting cells and tumor cells. They impair T cell function and NK cell function, promote tolerance, and induce apoptosis. However, monoclonal antibodies exist for PD-1, PD-L1, and PD-L2, like Keytruda for melanoma. Improves survival rates and shrinks tumors
Invariant NK T cells
Exhibit anti-tumor function. They express CD1d and can be activated by a-GalCer
NK cells and tumors
NK cells kill tumors via ADCC. They generate antibodies that bind to the surface of tumor cells. Augmented by NKG2D signals
Monoclonal antibodies
Uses B cells that are isolated from an immunized animal and immortalized by fusion with a tumor cell to form a hybridoma that produces a specific antibody
indefinitely. Individual hybridomas are separated, those
making antibody of desired specificity are identified and selected for propagation
Monoclonal antibodies and cancer diagnosis
Tumor cells express a variety of surface proteins. Monoclonal antibodies can use this feature of cancer cells to identify cancerous cells in biopsies and other cells. Microscopy and flow cytometry can be used, and combined with molecular analyses. This has proven essential for determining the course of therapy for each patient
Monoclonal antibodies and radiation therapy
May be able to conjugate antibodies with toxins or radioisotopes. The antibodies then deliver the toxins to cancer cells and away from normal, healthy cells and tissues. This would allow for greater precision with radiation therapy. There would be no need to pass through and damage tissues, as is the case with beam therapy
Herceptin
A monoclonal antibody that is given intravenously, used as a treatment for breast cancer that expresses the HER2 receptor (25% of cancers). The antibody induces internalization and degradation of HER2. This causes cell cycle arrest, suppression of angiogenesis, and induction of ADCC. Improves survival rates and lowers the risk of recurrence
Rituximab
An anti-CD20 humanized mAb for treatment of non-Hodgkin’s B-cell lymphoma and chronic lymphocytic leukemia (CLL). CD20 is widely expressed on B cells, from early pre-B cells to mature B cells, but not on other blood cells. In a study from 1994: ~50% of the patients treated
showed a regression of their lymphoma tumors. Binding of the antibody causes ADCC and complement activation
