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Lecture 1 Carcinogenesis and the Ten Hallmarks of Cancers Wong
CANCER STATISTICS:
• Second leading cause of death in the developed world after cardiovascular disease
o Leading cause of death in Canada
• The number of new cases continues to increase, but cancer mortality rates is decreasing
o Population aging is a major factor for the increases and the shift in cancer prevalence rates
o The cancers you are at high risk for is different in each age group
• Mortality (in descending order of the number of deaths in the developed world): lung, colorectal, breast, prostate, pancreatic cancer
WHAT IS CANCER?
• Cancer is defined as the loss of normal cellular growth control
• Cancer arises from a single transformed human cell
o Need rouge cell to have at least 7 important mutations
(or changes in the genome) to become a cancerous growth
• As a tumor grows, it will invade surrounding tissues and cause damage
• Through circulatory system, cancer can metastasize at distant sites
CANCER GROWTH:
CANCER CORRUPTS ITS SURROUNDING:
CANCER TENDS TO INVOLVE MULTIPLE MUTATIONS:
MUTATIONS AND CANCER: genes implicated in cancer
The prime suspects: But other mutations also occur:
• Oncogenes o Gas pedal = stuck on o Ex// RAS, myc
• Tumor suppressor genes o Brake = stuck off o Ex// p53 protein
• DNA repair genes o Ex// BRCA1 and 2
• Cell death genes
• Cell signalling genes
• Cell cycle checkpoint genes
• Cellular senescence genes
• Cellular differentiation genes
• Metastasis/invasion genes
• Carcinogen o Activating genes o Deactivating genes
• Cancer-related mutations can be inherited (germline) or occurred
during one’s lifetime (somatic)
NORMAL VS. CANCER GROWTH:
Lecture 1 Carcinogenesis and the Ten Hallmarks of Cancers Wong
THE TEN HALLMARKS OF CANCER: THE 10 CHARACTERISTICS OF CANCER CELLS THAT DIFFERENTIATE THEM FROM NORMAL CELLS
SUMMARY:
Loss of growth control
Promote (1) oncogene and (2) disrupt tumor suppression genes; with rapid growth, cancer cells lose cellular differentiation & organization and are unable to function normally
Extension of cellular lifespan
Cancers exhibit (3) cellular immunity and (4) suppression of apoptosis, the normal cellular mechanisms that limit the number of cell divisions, and can replicate indefinitely
Immune system interference
Cancers develop mechanisms to (5) evade or to (6) corrupt the immune system
Changes in metabolism
Cancers (7) switch their bioenergetics pathways to satisfy the growth demand
Mechanisms for spreading from local sites
Cancers turn on genes responsible for (8) angiogenesis and (9) invasion and metastasis for their escape
Genomic instability
Cancer cell exhibit (10) high mutation rate and aneuploidy (a change in the # of chromosomes)
PRINCIPLES OF ANTI-CANCER CHEMOTHERAPIES:
MECHANISMS OF ANTI-NEOPLASTIC DRUGS:
Affect cell survival • Attack various cellular processes that are crucial in cancer cell replication (cell cycle specific)
• Inhibit cell division (cell cycle specific)
• Damage genetic material i.e. DNA (non-cell cycle specific)
Affect cell growth signalling (non-cell cycle specific) • Endocrine therapy (tumor specific)
• Growth Factor inhibition
Boost the immune system in its efforts to combat the abnormal cells
CHEMOTHERAPEUTIC AGENTS IN THE CLINICS:
COMMON SIDE EFFECTS OF TRADITIONAL CANCER CHEMOTHERAPEUTICS:
Myelosuppression Hematopoietic stem cells are sensitive to the effects of many chemotherapeutic agents
• Anemia: low RBCs fatigue
• Neutropenia/leukopenia: low WBCs compromised immunity functions
• Thrombocytopenia: low platelet blood clotting defects
Elimination organ damage (liver, kidneys, and others)
• Cyclophosphamide and co-administration of Mesna
Nausea and vomiting • 5-HT3 receptor blockers + others
GI disturbances
Hair loss
CHEMOTHERAPY RESISTANCE:
ACQUIRED CHEMOTHERAPY RESISTANCE:
• Cancer cells that were once sensitive to a particular
drug can become tolerant
o Cross-resistance to multiple drugs can develop
• Directly related to their genetic instability
COMMON MECHANISMS OF DRUG RESISTANCE:
PHARMACOKINETICS PHARMACODYNAMICS
• Increase drug inactivation by tumor cells
• Decrease drug absorption/uptake
• Increase drug efflux
• Mutation of drug target
• Bypass cellular function of target
• Increase repair/tolerance to damage
MULTIPLE DRUG RESISTANCE IN HUMAN CANCER: P-glycoprotein (ATP-Binding Cassette (ABC) Transporter)
• There are several families of related ABC transporters; MDR-1, also known as P-glycoprotein (170 kDa), was the first ABC transporter identified
• Energy-dependent efflux pumps reduce intracellular drug concentration
o When the cancer is able to mutate this P-gp pump, it can efflux many types of chemotherapies
Lecture 1 Carcinogenesis and the Ten Hallmarks of Cancers Wong
ROLES OF THE IMMUNE SYSTEM IN CARCINOGENESIS AND ANTI-CANCER CHEMOTHERAPY:
FUNCTIONAL IMMUNE SYSTEM IS NEEDED TO PREVENT CARCINOGENESIS:
• Can damage or destroy some neoplastic cells
• Cytotoxic T cells recognize abnormal cells (neo-antigens) and destroy them
• Antibodies form in response to parts of the abnormal cell protein
• Interferons and tissue necrosis factor (TNF) play a role in the body’s attempt
to eliminate the abnormal cells)
(in absence of normal immune function, mice unable to remove minimal residual
disease, and tumor can recur)
AUGMENTING THE IMMUNE SYSTEM AS ANTI-CANCER THERAPIES:
• Synthetic monoclonal antibody therapies: label cancer cells for
immune system recognition and destruction
o Ex// trastuzumab, rituximab
• Immune-modulation therapies: promote T cell activity through the
removal of inhibitory and/or apoptosis signals
o Ex// ipilimumab, nivolumab
• Genetic engineering of TCR: personalized cancer therapy that used
the pt’s own T-cells to develop cancer recognizing T-cell progenesis
o Ex// CAR-T, YESCARTA
SUMMARY: CARCINOGENESIS AND OVERVIEW OF ANTI-CANCER CHEMOTHERAPY
• Cancer arise from the loss of normal growth control
• Cancer exhibits cellular immortality and genomic instability
• Normal immune functions is important to fight tumor formation in the body
• Development of tumors can take a long time and is divided into benign growth and cancerous/malignant growth
• Inherited or somatic mutations in members of three major gene classes are associated with the majority of human cancers
• Mechanisms of anti-cancer chemotherapies can be subdivided into the traditional agents (cell cycle specific & non-specific) and the new molecular targeted
therapeutic agents
• Anti-cancer chemotherapy is associated with many adverse side effects, most notably the suppression of normal blood-forming tissue functions
• Drug resistance invariably develops due to the strong selective pressure and cancer cells’ genomic instability
• Multiple cancer drug resistance is mediated by the over-expression of efflux pumps such as P-glycoprotein
• Optimal immune functions are necessary for successful clinical therapies against cancers
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