Biology of Cancer- Introduction

Incidence

Total number of new cases in a given time

Prevalence

Total number of cases at a give time

Mortality

Death caused by cancer

Carcinoma

• “-carcinoma” = Epithelial cells ( ~85% of cancers)

Sarcoma

• “-sarcoma” = Connective Tissue

Lymphoma

• “-lymphoma” = Cells of the lymphatic system

Leukemia

• “-leukemia” = Circulating blood cells

Benign

Benign tumors are confined to a certain area in the body

• Benign tumors are abnormally growing cells that do not invade other
tissues and remain restricted to a defined area

• Benign tumors are easier to treat (e.g surgery) and generally have
better prognoses
• Exceptions can be tumors in areas that are hard to reach surgically (e.g.
the brain

Malignant

• “Malignant” is an adjective to describe a property of
tumor cells. Malignant tumors have the ability to spread
throughout the body

-Malignant tumor cells break confinement and spread through the body
-Malignant cancers are abnormally growing cells that have gained
additional mutations that allow them to leave their tissue or origin

Metastasis

• “Metastasis” is a process. It says that tumor cells are
spreading through the body to form secondary tumors.
• Malignant tumors are tumors that have the ability to
metastasize

Carcinogenesis

• Carcinogenesis is the multi-step
process by which a healthy cells
transforms into a cancerous cell, and is
caused by:
• Inherited DNA mutations (Nature/Genetics)
• Environmental carcinogens (Environment)

Carcinogens

A carcinogen is any substance or agent that promotes the development of cancer

• Different environmental carcinogens are
related to different cancers
• UV = Skin cancer
• Cigarette smoke = Lung cancer
• Diet/Exercise
• Reproductive life = Breast cancer
• Alcohol = Liver cancer

Mutagens

Mutagens cause abnormal changes to DNA to disrupt normal cellular function

>Mutations to DNA sequence lead to changes in cell protein expression (function)

-Accumulated mutations are passed to new cells via mitosis

*All cancers have an underlying genetic component

Tumor Suppressor Genes

Tumor suppressor genes
• Non-mutated: Suppresses cancerous
pathways (e.g. cell cycle progression)
• Mutated: Fails to suppress cancerous
pathways

Proto-Oncogenes/Oncogenes

• An oncogene is a gene mutated such that its protein product is produced in higher quantities or has increased activity
• Non-mutated versions known as proto-oncogenes
• Mutated oncogenes promote tumorigenesis and cell cycle progression

Germline mutation

Germline mutations are inherited mutations and increase susceptibility

Somatic mutation

Somatic mutations are acquired mutations

Chemotherapy

Chemotherapy: Use of chemicals designed to kill cancer cells
• Better efficacy against malignant tumors

• Often associated with severe off-target effects

Radiation

Radiation: High energy targeted at tumor leading to death of tumor cells
• Ineffective against malignant tumors
• Potential off-target effects

Efficacy

Efficacy: How well do they treat (effect) the cancer

Safety

Safety: To what extent do they cause off target health effects

Therapeutic index

The therapeutic index
• Difference between minimum effective dose and maximum tolerated
dose
• Larger the value, safer the drug

Phosphorylation

Phosphorylation is one of the most common and impactful covalent
modification that affects enzyme activity

• Phosphorylation is the addition of a highly negative phosphate
groups (PO₄). The presence of this negative charge can have huge
effects on enzyme activity
• The addition of phosphates are catalyzed by enzymes called kinases
and the removal of phosphates are catalyzed by phosphatases

Kinases

Kinases are enzymes that add phosphate groups (phosphorylation)

The addition of phosphates are catalyzed by enzymes called kinases

Phosphatases

The addition of phosphates are catalyzed by enzymes called kinases
and the removal of phosphates are catalyzed by phosphatases

Phosphatases are enzymes that remove phosphate groups from molecules (dephosphorylation)

Critical Thinking Questions

1.) Why would a cancer have high incidence but low mortality? Why
would a cancer have low incidence by high mortality?

2.) Why do benign tumors generally have better prognoses than
malignant tumors?

3.) Why is surgery not enough for malignant cancers?

4.) Why can it be difficult to separate environmental and genetic causes of cancer?

1.) High incidence and low mortality it is very common but it is very treatable or potentially slow growing conversely, low incidence but high mortality means the cancer is likely aggressive/ fast growing and not very treatable.

2.) Benign tumors have better prognoses because they don’t metastasize and there for if they are in an optimal location they generally can be removed and there isn’t fear like malignant tumors some cells may have got left behind and it starts growing again

3.) Surgery is not an option for malignant tumors because they metastasize they are not located at just one site in the body rather they spread to different sites and invade healthy cells

4.) Without direct experiment it is difficult to separate environmental and genetic causes of cancer because genes and environment interact so its hard to distinguish the interplay where one starts and the other ends because environmental factors can cause mutations but how do you know what mutations are acquired vs inherited and how genetic predispositions affect how the environment affects you

Critical Thinking Questions

5.) In what ways do the principles of natural selection help explain the
acquisition of tumor resistance to therapeutics?

6.) In what ways would the genetic variability of cancers make cancers
difficult to treat?

7.) Why does it make sense that many inherited cancer susceptibility
genes often function in DNA repair pathways?

5.) Survival and reproduction of the fittest really because some of the cells may have some partial or full resistance and the therapeutics will kill the cells that have no resistance and this acts as a selective pressure meaning the resistant minority repopulates and becomes the majority and now the therapeutics no longer work.

6.) Genetic variability means that cancers would not all react to the same treatment even one cancer can be made up of genetic variable cells so there is no saying it can’t be or become drug resistant which means what works in one may case may not work for another

7.) It make sense that many inherited cancer susceptibility genes often function in DNA repair pathways because these pathways are crucial for removing defects and maintaining genomic stability so them not functioning allows these mutations accumulate which can leader to cancer

> EX: BRCA1/2 (homologous recombination) or MMR genes (mismatch repair) fix errors, and losing them creates genomic instability, allowing cancer-driving mutations to persist and transform normal cells

Nucleotide

Nucleotides are organic molecules acting as the fundamental building blocks of DNA and RNA, composed of a nitrogenous base, a five-carbon sugar, and a phosphate group

Hydrogen bonds

Hold together complementary base pairs in DNA

Phosphodiester bonds

Connect adjacent nucleotides through phosphate backbone in DNA

Glycosidic bonds

Connect nitrogenous base to deoxyribose sugar

Chromatin

• DNA strands are organized and compacted

• The organized form of DNA is called chromatin

• Refers to DNA packaged with proteins

• Chromatin is organized at multiple different layers

• Histones are the protein that is most important for DNA organization

Histones

Histones are the protein that is most important for DNA organization

Each nucleosome includes:

• Histone proteins (positively charged)

• DNA (negatively charged)

• Cells regulate DNA accessibility by altering the charges of histones

Chromosomes

Eukaryotes store DNA in the form of linear chromosomes

Gene

Genes make up a portion of the genome

• A gene is a specific sequence of DNA that encodes for either RNA or Protein

Promoter

Promoters are regions of DNA upstream of a gene that regulate the level of gene expression

Depurination

• Depurination: Spontaneous loss of purines (Guanine/Adenine)

Deamination

• Deamination: Spontaneous loss of an amine groups (converts cytosine to uracil)

Free Radicals/ROS

• Most biological free radicals involve the element oxygen and are called reactive oxygen species (ROS)

• Results from oxygen’s high electronegativity

• Free radicals/ROS are very reactive and tend to steal electrons from the first chemical they interact with

• Stealing electrons from DNA can cause random chemical conversions of nucleotides

Ultraviolet radiation

• Radiation is a form of energy that can cause chemical reactions in DNA

• Not all forms of radiation have enough energy to cause mutation (e.g. visible light is a form of radiation) • High energy forms of radiation can cause DNA damage

• X-rays can cause damage, but only after long and repeated exposure

• The most common form of cancer-causing radiation are Ultraviolet (UV) radiation

• Classified as UV-A, -B, and -C

• UV-B most commonly associated with carcinogenesis

Pyrimidine Dimers

• Energy from UV radiation is absorbed in aromatic rings

• The most common result is the formation of pyrimidine dimers between two adjacent pyrimidine nucleotides

Hormones/Estrogen

Endogenous hormones can act as carcinogenes

• Our body’s natural chemical hormones can stimulate cell proliferation

• Hormone-related cancers include Breast, Endometrial, Ovarian, Prostate, Testicular, Thyroid

• Estrogen is a hormone that stimulate cell proliferation in breast tissue during pregnancy

• During cancer, estrogen can stimulate cancers cell proliferation

Indel

Chromosome Translocation

Silent Mutation

Missense Mutation

Nonsense Mutation

Frameshift Mutation

Driver/Passenger Mutation

Base Excision Repair

Glycosidases

PARP enzymes

Nucleotide Excision Repair

NER Endonucleases

Mismatch Repair

hMut Proteins

Double Strand Breaks

Homologous Recombination

ATM proteins

Non-homologous End Joining

Critical Thinking Questions

1.) What are the three different types of bonds found in a DNA molecule?

2.)What are the three different sources of DNA mutation discussed in class?

3.) What is the difference between germline and somatic mutations?

4.)What are some examples of intrinsic mutation mechanisms discussed in class?

Critical Thinking Questions

5.) What are some examples of environmental mutation mechanisms discussed in class?

6.) What are the two ways in which viral infection could lead to carcinogenesis?

7.)What are the different ways that mutations can affect DNA sequence?

8.)What are the different ways that mutations can affect protein sequence?

Critical Thinking Questions

9.) What are the four DNA repair pathways discussed in class? What is a protein that is associated with each pathway?

10.) Why do base excision repair pathways require a glycosidase and nucleotide excision repair pathways require an endonuclease?

11.) Why would it be the case that many germline/inherited cancer susceptibility genes play a role in DNA repair?

12.)Why can the induction of DNA damage both cause cancer and be used as a therapeutic for treating cancer?