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