JHU - Introduction to the Biology of Cancer

Last updated Mar 6, 2023

• Type note
• Status needs revision
• Source course
• On biology
• On cancer

Metadata

• Source:: Introduction to the Biology of Cancer | Coursera
• Instructor:: Kenneth Pienta
• Offered by:: Johns Hopkins University
• Platform:: Coursera
• Publish Date::
• Review Date::

About this Course
The course introduces the molecular biology of cancer (oncogenes and tumor suppressor genes) as well as the biologic hallmarks of cancer. The course also describes the risk factors for the major cancers worldwide, including lung cancer, breast cancer, colon cancer, prostate cancer, liver cancer, and stomach cancer. We explain how cancer is staged, the major ways cancer is found by imaging, and how the major cancers are treated.

In addition to the core materials, this course includes two Honors lessons devoted to cancers of the liver and prostate.

Upon successful completion of this course, you will be able to:

• Identify the major types of cancer worldwide. (Lecture 1)
• Describe how genes contribute to the risk and growth of cancer. (Lecture 2)
• List and describe the ten cellular hallmarks of cancer. (Lecture 3)
• Define metastasis, and identify the major steps in the metastatic process. (Lecture 4)
• Describe the role of imaging in the screening, diagnosis, staging, and treatments of cancer. (Lecture 5)
• Explain how cancer is treated. (Lecture 6)

We hope that this course gives you a basic understanding of cancer biology and treatment. The course is not designed for patients seeking treatment guidance – but it can help you understand how cancer develops and provides a framework for understanding cancer diagnosis and treatment.

• Weinberg RA. The Biology of Cancer**, 2nd Edition Garland Science: May 18, 2013.**
  • This book provides an in-depth description of all the topics touched on in this course. It requires a basic knowledge of biology.
  • http://www.amazon.com/The-Biology-Cancer-2nd-Edition/dp/0815342209
• MukherjeeS. The Emperor of All Maladies: A Biography of Cancer Scribner: Aug 9, 2011)
  • This book provides a history of cancer and how it affects us. It does not require any prior knowledge of biology.
  • http://www.amazon.com/The-Emperor-All-Maladies-Biography/dp/1439170916
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011 Mar 4;144(5):646-74. PMID: 21376230.
  • This article is available free to the public and describes the hallmarks of cancer.
  • http://dx.doi.org/10.1016/j.cell.2011.02.013
• Cavallo F, et al. 2011: the immune hallmarks of cancer. Cancer Immunol Immunother. 2011 Mar;60(3):319-26. PMID: 21267721.
  • This article is available free to the public and describes how the immune system relates to the hallmarks of cancer.
  • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042096/
• Tennat DA, et al. Metabolic transformation in cancer. Carcinogenesis**. 2009 Aug;30(8):1269-80. PMID: 19321800**
  • This article is available free to the public and describes how cancer cells use metabolism differently than normal cells.
  • http://dx.doi.org/10.1093/carcin/bgp070
• Pienta KJ, et al. The cancer diaspora: Metastasis beyond the seed and soil hypothesis. Clin Cancer Res**. 2013 Nov 1;19(21):5849-55. PMID: 24100626.**
  • This article is available free to the public and describes how cancer cells metastasize.
  • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835696/

• It means “uncontrolled growth” ^3cbfcc
  • The disease is caused by an uncontrolled division of abnormal cells in a part of the body.
• Also referred to as a “tumor” ^331dbd
  • A swelling of a part of the body, generally without inflammation, caused by an abnormal growth of tissue, whether benign or malignant.
• Also referred to as a “neoplasm” ^1ab7e0
  • A new and abnormal growth of tissue in some part of the body.
• Cancer is a genetic disease.
  • It is caused by an accumulation of detrimental variation in the genome over the course of a lifetime.
  • Most of the time, a single mutation is not sufficient to induce cancer formation.

• From Greek karkinos, “a crab”
  • Greek physicians Hippocrates and Galen, among others, noted the similarity of crabs to some tumors with swollen veins.
• From Latin cancer, “a crab”, later, “malignant tumor”
• Old English cancer, “spreading sore, cancer”

• The term oncology literally means a branch of science that deals with tumors and cancers.
• The word “onco” means bulk, mass, or tumor, while “-logy” means study.

• From Greek metastasis, “a removing, removal; migration; a changing; change, revolution”
• Now refers to the spreading of cancer from a primary site to distant organs.

• Cancers are classified according to the tissue where they originate
• There are four main types
  • Carcinoma
    • Arise in epithelial tissue that is found in the internal and external lining of the body
    • Adenocarcinomas develop in an organ or gland
    • Squamous cell carcinomas develop in the squamous epithelium of organs, including the skin, bladder, esophagus, and lung
  • Sarcoma
    • Arise from connective tissue that is found in bones, tendons, cartilage, muscle, and fat.
  • Leukemia
    • Cancers of the blodd that originate in bone marrow.
  • Lymphoma
    • Cancer of the lymph system

• Most common cancer in men and women
• Leading cause of cancer death
• 85% of lung cancers are non-small-cell cancers (NSCLC)
• Smoking is the leading cause of lung cancer ^cbc1dd
  • 87% of lung cancer deaths in men and 70% in women are likely caused by smoking
  • Risk of developing lung cancer is 25-times higher in smokers as compared to nonsmokers.
  • Many others are linked to secondhand smoke
• Other risk factors include Radon, asbestos, arsenic, radioactive ores, inhaled chemicals.
• Lung cancer prevention is relatively straightforward:
  • Smoking cessation
    • Stop smoking
    • Don’t let yourself get exposed to secondhand smoke.
  • Decreasing exposure
    • If you’re mining ore, wear gloves and protective gear.
    • Doesn’t really apply to normal people like myself.

• Colon is a five-foot-long tube at the end of the digestive system that stores waste
• Rectum is the last 6 inches of the colon
• Third most common cancer in men and women
  • Approximately 93,000 diagnoses per year in the US
• Third leading cause of cancer death
• Most primary colon cancers are adenocarcinomas.
• Risk factors of colon cancer
  • Age
    • 9 out of 10 people diagnosed ith colon cancer are over 50 years old
  • Diet
    • High in red meats
    • Low in vegetables
    • If you don’t eat a lot of vegetables, you don’t have a lot of fiber cleaning out the colon as it traverses through, allowing damage to the colon over your lifetime.
  • Lifestyle
    • Obesity
    • Smoking
    • Alcohol
  • Inflammatory bowel disease
  • Positive Family history
  • Genes
• Prevention for colon cancer
  • High-fiber diet is associated with decreased risk of developing colon cancer
  • Possibility: Low-dose aspirin
    • It’s unclear why it’s effective.
    • It’s not recommended on wide basis.
• Screening of colon cancer
  • Colonoscopy every 5–10 years starting at age 50.
  • Other potential tests
    • Guaiac-based fecal occult blood test
    • Stool DNA test
    • Sigmoidoscopy
    • Double contrast barium enema

• The breast consist of milk-producing glands surrounded by fat and connective tissue. The glands connect to ducts which carry milk out to the nipple.
• Breast cancer is generally adenocarcinoma.
• Most common cancer in US women.
• Second leading cause of cancer death.
• Breast cancers are classified by their location and by their histologic (tissue or cellular) subtype. 70% to 80% of primary breast cancers are infiltrating ductal cancers, followed by lobular and nipple cancers.
• Risk factors of breast cancer
  • Age
    • One-eighth of breast cancers are in women under 45; two-thirds are in women over age 55.
  • Positive Family History
  • Genes
  • Dense breast tissue
    • May make mammograms less accurate
  • Lifestyle
    • Obesity, inactivity, alcohol use, not having children, oral contraceptive use, post-menopausal hormone therapy
• Prevention of breast cancer
  • No known proven strategies
    • Except for prophylactic mastectomy in high-risk women
  • Possibilities (things that might work)
    • High-fiber, low-fat diet
    • Staying physically active
    • Maintaining normal weight
• Breast Cancer Screening
  • Monthly self-exams
  • Yearly exams by health practitioner
  • Mammograms
  • Potentially: MRI, ultrasound

• The prostate is a gland about the size of a walnut that sits below the bladder.
  • It is only found in men.
  • The prostate is thought to help protect the urinary tract from infections.
• Most common cancer in men
  • One in 7 men in the US will be diagnosed in their lifetime
• Second leading cause of cancer death in men.
• Prostate Cancer Risk Factors
  • Age
    • Occurs mainly in older men.
  • Ethnicity
    • Higher in African American men, lower in Asian men
  • Family history
  • Genes
    • HoxB13
    • BRACA1,2
    • MSH2 and MLH1
  • Diet
    • High in red meat
    • low in vegetables
• Prostate Cancer Prevention
  • No known proven strategies
  • Possibilities
    • High-fiber, low-fat diet
    • Staying physically active
    • Maintaining normal weight
• Prostate Cancer Screening
  • Yearly digital rectal exam starting at age 50

• The liver is a large gland that sits right below the rib cage on the right side.
  • Processes nutrients absorbed from the intestine
  • Makes clotting factors
  • Secretes bile to help the body absorb fats
• One of the most common cancers worldwide
• A leading cause of cancer death worldwide
• Liver Cancer Risk Factors ^891718
  • Sex
    • Approximately twice as common in men
  • Chronic viral hepatitis
  • Alcohol
  • Aflatoxins
    • Fungus associated with storing grains in tropical environments
  • Lifestyle
    • Obesity, anabolic steroids, smoking
• Liver Cancer Prevention
  • Prevent and treat hepatitis infections
  • Avoid alcohol abuse
  • Avoid smoking
  • Avoid obesity
• Liver Cancer Screening
  • No proven strategy

• The stomach holds food and starts the process of digestion
• Common cancer worldwide
• A leading cause of cancer death worldwide
• Stomach Cancer Risk Factors
  • Sex
    • Approximately twice as common in men
  • Age
    • Most people are diagnosed over the age of 60
  • H. pylori
    • Chronic infection with this bacteria appears to cause stomach cancer
  • Diet
    • Smoked foods, salted fish and meat, and pickled vegetables (high nitrates and nitrites)
  • Lifestyle
    • Obesity, smoking
  • Type A blood
    • Reason unknown
• Stomach Cancer Prevention
  • Treat H. pylori infection
  • Refrigeration instead of salting/pickling
  • High-fiber diet
  • Avoid smoking
  • Maintain a good body weight
• Stomach Cancer Screening
  • No proven strategy

• The number one risk factor of cancer is smoking.
• Obesity and diets that are low in fiber and high in red meat contribute to most cancers.
• Alcohol abuse is a common risk factor across many cancers.
• So to summarize prevention strategies, don’t smoke, don’t smoke, don’t smoke.
• And, in addition, being physically active and maintaining a normal weight, as well as eating a heart-healthy diet that is low in red meat and high in fiber are the best ways to decrease risk of developing cancer.

• Cancer is a genetic disease.
  • It is caused by an accumulation of detrimental variation in the genome.
  • A single mutation is not sufficient to induce cancer formation.
• A gene is a discrete unit of heredity of a living organism.
  • First found by Gregor Mendel, father of genetics, while studying pea plants, published in 1866.
• In molecular biology, a gene is said to be a region of DNA that encodes for a functional product (RNA or protein).
• Humans have ~25,000 genes in the genome.
• DNA
  • Deoxyribonucleic Acid
  • Provides instructions for all processes.
• Every time a cell divides, it must replicate its DNA.
• DNA is packaged into chromosomes.
• Humans are diploid.
• Genomes = all the genes of an organism.
• The Central Dogma of molecular biology:
  • Every time a cell divides, it makes a copy of its DNA to give to its daughter cells.
  • The “code” of the DNA genes is transcribed or copied, into RNA.
  • The copy of the “code” (RNA) is translated into protein that then does the work of the cell.
• Even though every cell has the same DNA, only a subset of genes are transcribed into RNA.

• Most genetic variation is benign.
  • 99.5% of our genomes are the same person to person — 0.5% is variable in the human population.
  • Most variation is small — only one or a few bases of the DNA vary at any particular location
  • Variation in our genomes accounts for our individuality. No one shares the exact copy of our DNA.
  • Even your alleles may differ from each other — one variant on your maternal allele and a different variant on your paternal allele.
• What is a mutation?
  • A mutation is a detrimental genetic variation that increases the risk of developing a disease or, in rare diseases, causes the disease.
• There are two different types of cancer genes:
  • Oncogene
    • Promotes cancer
  • Tumor suppressor
    • Protects against cancer
• There are two types of mutation:
  • Activating
    • Causes the gene to be expressed at the wrong time, at the wrong level, or with a new function
    • Activating mutations in oncogenes are tumorigenic
  • Inactivating
    • Causes reduced function of a gene (less RNA or protein is made)
    • Inactivating mutations in tumor suppressors are tumorigenic

• Where do mutations come from?
  • Somatic mutations are acquired by a somatic cell (all cells except eggs or sperm) that are passed on to daughter cells during cell proliferation. These mutations cannot be inherited by offspring.
    • Every time a cell divides, it must replicate its DNA.
      • Errors get made by change: ~1 mutation every 10 billion base pairs
    • Increased DNA damage and replication error can be due to environmental carcinogens
      • UV damage (repeated sunburn) to skin cells
      • Smoking causes chemical damage to lung cells
      • Hepatitis and alcohol abuse lead to damaging cirrhosis of liver cell
  • Germline mutations (aka inherited mutations) are present in a germ cell (egg or sperm) and are inherited by offspring — genetic variation we are born with
    • Germline variations accounts for why offspring look similar (but not identical) to their parents
    • When cancer “runs in families”, it may be due to inherited mutations
• Two-Hit Hypothesis
  • This describes why not all women with a BRACA1/2 mutation get breast cancer.
  • Humans have two copies of every gene (diploid) — one maternal, one paternal.
  • Even if one copy (allele) of the gene is mutated, the other copy allows the protein to operate normally.
  • For a gene to be cancer inducing, both copies of the gene must be affected. The second “hit” may alter the DNA (mutation) or alter the expression of the DNA (epigenetic).
• Most cancers require mutations in multiple different types of genes
  • To survive, a cancer cell must overcome normal regulation of:
    • Cell proliferation
    • Cell survival
    • Cellular communication
  • Each of these processes is tightly regulated in normal cells by redundant pathways
  • To become cancerous, a cell must accumulate mutations (minimum 6–7) in multiple different genes
• Cancer cells show a great deal of genomic instability
  • Genomic stability describes how cells can survive and divide with higher rates of mutation than normal cells.
  • Normal cell: DNA replication error —>programmed cell death
  • Cancer cell: DNA replication error —> cell continues to divide and passes mutation
  • As mutations in these repair pathways accumulate, the frequency of mutations in the cancer cell genome increases

• Apoptosis: A form of programmed cell death
• Mitosis: A form of cell division that results in two daughter cells
• Telomeres: Located at the ends of a chromosome, these have a specific sequence of nucleotides; shorten after each mitotic cycle
• Angiogenesis: The process of developing new blood vessels from pre-existing blood vessels
• Metastasis: The process by which cancer spreads from its origin to another part of the body

• The cell (Latin cella, meaning “small room”) is the smallest functional unit of life that replicates independently
• This replication is called mitosis, and it is tightly controlled
• Cells make up the body’s tissues
• Organs of the body are comprised of tissues

All hallmarks of cancer promote metastasis

The Ten Cellular Hallmarks of Cancer:

• Normal human cells have finite ability to undergo mitosis due to the end replication problem
  • This is largely due in part to ends of chromosomes (telomeres) shortening after each mitotic division
  • Once normal human cells reach the Hayflick’s limit, cells can go into cellular senescence ($G_0$ phase of cell cycle).
• Cancer cells are very different — they can greatly exceed “Hayflick’s limit” and continue to undergo mitosis
  • Cancer cells are able to do this because they can elongate their telomeres using an enzyme called telomerase.
  • Cancer cells are able to continue mitotic divisions because chormosomal ends (telomeres) are extended repeatedly by the enzyme telomerase

• Normal eukaryotic cells have 23 pairs of chromosomes per cell, stored in the nucleus.
• If a mutation is detected in a normal cell undergoing DNA synthesis, the cycle will arrest and the mutation repaired before re-entering the cell cycle.
• This is regulated by genes known as tumor suppressors.
  • You can think of these genes as “brakes” in your car.
• Cancer cells are different and can have an abnormal amount of chromosomes per cell and can bear mutations in their DNA with the ability to still undergo mitosis.
• Genes commonly mutated or lost are tumor suppressor genes (TSGs)
• Genes that get over-expressed are known as oncogenes, which cause cells to proliferate uncontrollably
• Notable gene alterations observed in cancer are point mutations, the deletion of regions of chromosomes, loss of heterozygosity (LOH), and several others

• Mitosis in normal cells is a tightly controlled process, wherein the proand anti-proliferation signals coordinate cell activities at the cell cycle level.
• However, due to Hallmark No. 2 (genomic instability), most cancer cells circumvent normal growth suppressor signals in the G1 checkpoint in order to continue proliferating.
• How cancer cells evade growth suppressor signals?
  • A TSG called retinoblastoma (Rb) inhibits the normal cell’s passage though the restriction point in the G1 cell cycle phase.
  • Another TSG, p53, functions as a central regulator of cell death because it arrests the cell cycle upon detection of DNA damage.

• Normal cells can initiate apoptosis (cell death) in response to abundant DNA damage and other cellular stresses
• In contrast, cancer cells are generally less sensitive to DNA damage, growth factor deprivation, treatments, and similar stresses, and so they tend to avoid apoptosis.

• Within normal cells, growth factor signaling is also tightly controlled to allow for cellular and tissue homeostasis.
• Cancer cells have the ability to proliferate due to the aforementioned Hallmarks 1–4 as well as to over-active oncogenes such as RAS.
• Cancer cells can also stimulate normal cells in the microenvironment to provide growth factors.

• For cancer cells to sustain uncontrolled cell proliferation (Hallmark No. 5), the cells must adjust their energy production.
• Cancer cells can do this by finding and using alternate sources for energy and alternate metabolic pathways.
• Normal cells break glucose down (glycolysis) to pyruvate which provide energy adenosine triphosphate (ATP) for the cell
• Cancer cells are very different — these cells can convert glucose to lactate irrespective of oxygen.
• This allows the cancer cell to divert metabolites for useful anabolic processes such as mitosis.

• The ever-alert immune system surveils the human body to destroy viruses, pathogens, and other foreign cell types, including tumor cells.
• Cells of the immune system that engulf and destroy foreign particles are B cells (secrete antibodies and cytokines), T lymphocytes, macrophages, and natural killer cells.
• Cancer cells can protect themselves by inhibiting T cells that would normally attack these cancer cells.

• The tumor microenvironment (surrounding environment of the tumor) is often infiltrated by cells from the immune system cells that enable tumors to mimic inflammatory conditions seen in the normal tissues.
• Immune cells provide the tumor cells with essential factors that allow them to survive, move, proliferate, and undergo epithelial-to-mesenchymal transition (EMT) and invade.

• All tumor cells require a blood supply to grow to a significant size.
• Cancer cells are able to survive by inducing the formation of new blood vessels from pre-existing ones (angiogenesis).
• Pro-angiogenic factors such as vascular endothelial growth factor (VEGF) become activated in tumor cells and signal endothelial cell proliferation and growth of blood vessels.
  • Immune infiltrating cells can also induce this.
• New Blood Vessel Formation
  • Tumor cells grow more quickly than normal cells and outgrow their source of nutrients — blood.
  • They make new blood vessels to provide necessary nutrients and oxygen.
  • Newly formed tumor vessels tend to be leaky.
  • These new vessels provide a way for tumor cells to get into the bloodstream.

• Cell-cell and cell-extracellular matrix interactions are altered.
• Changes in or loss of structural proteins (e.g. integrins).
• Loss of genes known as metastasis suppressor genes (KAI1 / CD82, NDRG1)
• Recruitment of immune cells
• Epithelial-to-mesenchymal transition (EMT)

• Tumor cells are able to break through the extracellular matrix (ECM) during invasion and are able to migrate outwardly, away from their natural location.
• Invasion allows cancer cells to more toward blood vessels.

• Cancer cells enter the bloodstream. ^bc375c
  • Actively: by pushing their way through endothelial cells.
  • Passively: tumor cells are shed from a tumor and enter presumably leaky blood vessels.

• Cell must traverse the venous system, lungs, and arterial system. ^7b1e1e
• Tumors that are circulating in the bloodstream are called circulating tumor cells, or CTCs.
• During this transit, these cells must avoid various sources of cellular death.

• Cells begin growing in the secondary site into metastatic tumors.
• These cells may not begin to divide immediately when they get to their destination. They may go dormant and grow into a tumor later.

• Metastasis word can be broken down into two parts
  • Meta: alter, beyond
  • Stasis: state of inactivity, stagnation
• The process by which tumor cells move from the primary tumor to a different organ via lymph and/or blood
  • Example: prostate cancer cells metastasize to bone.
• Terms to know
  • Metastasize
    • verb: act of moving from primary tumor to secondary organ
  • Metastatic
    • adjective: the state of being able to metastasize
  • Metastases
    • noun: multiple metastatic tumors
• Benign tumors are masses of cells that are unable to invade neighboring tissue or metastasize.
• Malignant tumors are cancerous masses of tumor cells that are able to invade neighboring tissue and metastasize.
• The ability to metastasize is what makes a tumor malignant.
• All solid tumors can metastasize.
• Most people who die of cancer will have a metastatic lesion.

• The term “metastasis” was first used in various writing in the 18th and 19th centuries to describe breast cancer “metastasis of milk”, which was metastatic tumors growing in lactating women. (Gould and Pyle, 1898)
• “Metastasis” or “metastase” in the context of diagnosing and treating cancer was used first in 1829 by French surgeon J. C. Recamier.
• Tumor dissemination was described in 1858 by German doctor and biologist Rudolf Virchow.

• Loss of tissue function in the metastatic site
• Bleeding: up to 10% of advanced cancer patients experience bleeding
• Pulmonary embolism: blocked artery in the lung due to tumors
• Infection: due to the cancer damaging immune arsenal, or the cancer treatment.
• Cancer treatments can cause irreparable damage
  • including treatments for pain.
• Cachexia: weakness and wasting of the body due to severe chronic illness.
• Systemic disruption of ion homeostasis (e.g., hypercalcemia)

• The TNM staging system is the most commonly used staging system in cancer diagnosis.
• TNM stands for Tumor Lymph Node Metastasis.
• Tumor
  • Tumor staging describes the size of a person’s tumor.
    • Determined via physical exam, imaging, surgery.
• Lymph Node
  • Lymphatic vessels carry lymph fluid to lymph nodes and then to the bloodstream.
  • Its purpose is to drain excess fluid to maintain volume and composition to tissue; to act as a defense against infection.
  • Lymph is interstitial fluid (fluid from between cells), composed of
    • Water
    • White blood cells (immune cells)
    • Proteins, fats, sugars, salts
    • Cellular waste
  • TNM system is typically binary when it comes to the presence of cancer in lymph nodes.
  • N = 0 means no cancer has been found in the lymph node.
  • N = 1 means cancer has been found in the lymph node.
  • When cancer if found in the lymph node beyond the local region, it represents the worst diagnosis and prognosis.
• Metastasis
  • This determines whether cancer has spread to other regions or not.
  • Once cancer has reached metastatic capability, it has become quite aggressive and most likely fatal.
• TNM Staging Example: Prostate Cancer
  • T3N1M1b is worse than T1N0M0

• Accumulated mutations cause a cell to start changing
  • Uncontrolled cell division
  • No growth suppression
  • Different metabolism
  • Resistant to cell death
  • Avoiding immune destruction
• Cells grow uncontrollably until they become a mass; some never become metastatic.

• Tumor cells grow more quickly than normal cells and outgrow their source of nutrients — blood.
• They make new blood vessels to provide necessary nutrients and oxygen.
• Newly formed tumor vessels tend to be leaky.
• These new vessels provide a way for tumor cells to get into the bloodstream.

• Epithelial cells
  • cuboidal, stationary, strong interactions with ECM and other cells.
• Extracellular matrix (ECM)
  • molecules secreted by cells that provide structure and biochemical support to surrounding cells.
• Mesenchymal cells
  • stretched shape, mobile, weak/no interactions with ECM or other cells.

• Tumor cells break through the ECM during invasion and are able to migrate outwardly, away from their natural location.
• Invasion allows cancer cells to move toward blood vessels.

^bc375c

Key Step 3: Survival during Systemic Circulation

• Surviving CTCs eventually leave the bloodstream by either:
  • getting stuck in capillaries
  • becoming attracted to a secondary site via secreted molecular factors
• Once they get to a secondary site, they become known as disseminated tumor cells (DTCs).

• Many DTCs begin growing in the secondary site into metastatic tumors.
• DTCs may not begin to divide immediately when they get to their destination; they may go dormant and grow into a tumor later.

• “The distribution of secondary growths in cancer of the breast” (published in 1889)
• Cancer cells (“seeds”) home to certain secondary sites because they thrive better in that environment (“soil”)
  • Example: prostate cancer cells grow very well in the bone marrow, but prostate metastases are never found the pancreas.

• Medical imaging: The technique and process of creating visual representations of the inside of a body for clinical analysis and medical intervention.
  • Or, simply, to take pictures inside the body in order to diagnose and treat disease.
• 2D images show us the length and width of structures.
• 3D images will show us the depth, as well as the length and width; this allows us to see the relationship between structures.
• 2D Image Projections
  • Usually taken in 1 or 2 projections
    • Back to front (posterior to anterior)
      • or reverse, i.e. front to back (anterior to posterior)
    • Side view (lateral)
  • 
• 3D Image Projections
  • a.k.a. Cross Sectional Imaging
  • Based on the anatomical planes of the human body
    • Transverse (axial)
      • Separates head from feet
    • Frontal (coronal)
      • Separates front from back
    • Lateral (sagittal)
      • Separates right from left
  • 
• Contrast Agents
  • a.k.a. contrast media, X-ray dye
  • Used to differentiate structures of similar densities
  • Usually given orally, or through a vein (IV) or artery (IA)
  • Common contrasts agents are iodine and barium

• If we categorized by the type of energy used to produce the image, there are only four basic types of energy:
  • X-rays
    • Plain films, CT (computerized axial tomography), etc.
  • Magnetic field
    • MRI (magnetic resonance imaging)
  • Sound waves
    • Ultrasound
  • Radioisotopes
    • Nuclear medicine
• X-rays are short wavelength electromagnetic (EM) radiation
  • EM radiation results when an electric field and a magnetic field produce synchronized waves (EM waves).
    • EM waves, characterized by wavelength, form a spectrum of wavelengths.
      • From longer wavelengths with less energy (less penetrating)
      • To shorter wavelengths with more energy (more penetrating)
  • X-rays, at the far right of the spectrum, can penetrate the body.
• How sound waves are used to produce images:
• How a magnetic field is used to produce MRI images:
• How a radionuclide is used to produce nuclear medicine images:

• Imaging in Cancer is quite important as the five cancer management techniques out of 6 involve imaging:
  • Keep it away (cancer prevention)
  • Watch out for it (cancer screening)
  • If we think it’s there, we determine if it is (cancer diagnosis)
  • If we know it’s there, we determine how advanced it is (cancer staging)
  • Once we have treated it, we check to see if treatment worked (assess treatment response)
  • After treatment, we keep watch (monitoring)
• Cancer Screening
  • Screening tests are done to find cancer at an early stage — before symptoms appear — when it may be easier to treat and possible to cure.
  • Screening tests should be inexpensive and safe, with low risk and high benefit.
  • In common cancers, imaging used in screening:
    • Lung: CT scans
    • Colon: not first choice, plain films (barium enema)
    • Breast: Mammography
    • Prostate
    • Liver: Ultrasound
    • Gastric
• Cancer Diagnosis
  • Pathology is the “gold standard” in cancer diagnosis.
  • Imaging is generally part of a cancer diagnostic work-up and is used to support the diagnosis.
  • Biopsies of the lung, breast, and liver may be image guided.
• Cancer Staging
  • Tropism: When cancer cells extravasate, they “home” to different organ sites, i.e., Paget’s hypothesis — cancer cells (“seeds”) go to certain sites where they will thrive (“soil”).
  • 
• Imaging Assessment of Treatment Response
  • Imaging is used to assess change in tumor burden (tumor shrinkage) in response to treatment.
  • Purpose: To guide cancer treatment
    • Example: RECIST (response evaluation criteria in solid tumors) guideline
      • CR (complete response): Disappearance of all target (treated) lesions.
      • PR (partial response): 30% decrease in size of sum of target lesions.
      • PD (progressive disease): 20% increase in sum of target lesions.
      • SD (stable disease): Smaller changes that do no meet above criteria.
• Monitoring after therapy with Imaging
  • At the completion of treatment, use the imaging modality that best characterized the cancer at baseline to monitor for recurrent cancer.
  • Exploit cancer hallmarks to monitor patients after therapy.

• Previously, we’ve learned that most people who die from cancer had a metastatic tumor.
• However, historically, reports exist of patients with limited metastatic cancer, who were treated and cured.
• 1994: The state of limited metastatic potential, termed oligometastasis.
• Since 1994: Due to improved imaging and novel treatment options, more patients designated as oligometastatic.
• There is a spectrum in which metastasis occurs.
• Within that spectrum is a place where metastasis is more “laid back” — oligometastasis.
• Oligometastasis can be diagnosed during staging with imaging.
• An oligometastatic diagnosis means treatment intent may be to cure.

• Main types of treatment
  • Surgery
  • Radiation
  • Hormonal therapy
  • Chemotherapy
  • Targeted therapy
  • Immunotherapy
• Surgery and Radiation
  • Approximately 50% of all people diagnosed with cancer in the US are cured by surgery or radiation because the cancer is removed or killed by radiation before it has spread.
  • These therapies provide the backbone for all cancer therapy
    • Surgery removes the tumor.
    • Radiation can be given as external beam radiation or by implanting radioactive seeds into the tumor.
  • External Beam Radiation Therapy
    • Usually given in several doses or fractions over time
    • Can be equally as curative as surgery
    • Can be used for palliation
    • Radiation kills dividing cells through DNA damage, which leads to cell death.
  • Therapies in combination with surgery or radiation
    • Neoadjuvant therapy
      • A therapy (usually a chemotherapy) given before surgery or radiation to th primary cancer.
    • Adjuvant therapy
      • A therapy (usually a chemotherapy) given after surgery or radiation to the primary cancer
    • Neoadjuvant —> Surgery —> Adjuvant
• Hormones
  • Your body makes chemical (hormones) that tell various organs what to do
    • The female hormone estrogen controls the development of female secondary sexual characteristics, e.g., breast growth, regulation of menses.
    • The male hormone testosterone tells male reproductive tissues such as the testis and prostate to grow and promotes increased muscle, bone mass, and body hair.
• Hormone Therapy
  • Hormones can contribute to the growth of cancer
    • The female hormone estrogen stimulates breast cancer growth
      • Anit-estrogen agents are used to help treat breast cancer
    • The male hormone testosterone stimulate prostate cancer growth
      • Anit-testosterone agents are used to treat prostate cancer
• Chemotherapy
  • Almost all chemotherapy drugs have been designed to keep cells from dividing. Cancer cells tend to divide more rapidly than normal cells and, therefore, they are more likely to die from the treatment.
  • Normal cells in the body — like cells in the hair follicle, white blood cells that fight infection, and cells in the lining of the colon — are also dividing, and that is why the main side effects of chemotherapy are hair loss, infection risk, and nausea/diarrhea.
  • There are two broad classes of chemotherapy drugs
    • Agents that interfere with replication of DNA
      • Metals: Platinum agents — cisplatin, carboplatin, oxaliplatin
      • Anti-metabolites: 5-Fluorouracil (5FU), capecitabine (Xeloda), gemcitabine (Gemzar), pemetrexed (Alimta)
      • Alkylators: Cyclophosphamide (Cytoxan)
      • Antibiotics: Doxorubicin (Doxil)
        • Topoisomerase inhibitors — etoposide (VP-16), irinotecan (Camptosar)
    • Agents that interfere with cell division by blocking mitosis
      • 
      • Vinca alkaloids
        • Vinorelbine (Navelbine)
        • Others: vinblastine and vincristine
      • Taxanes
        • Docetaxel (Taxotere)
        • Paclitaxel (Taxol)
        • Cabazitaxel (Jevtana)
• Targeted Therapy
  • Targeted therapy inhibits proteins that are mutated or overexpressed and helping the cancer to grow — this makes the therapy more “cancer specific”
    • VEGF (vascular endothelial growth factor)
    • EGFR (epidermal growth factor receptor)
    • HER2
    • ALK (anaplastic lymphoma kinase)
    • MTOR (mechanistic target of rapamycin)
    • CDK (cyclin-dependent kinase) 4 and CDK 6
• Immunotherapy
  • Immunotherapy is the use of medicine to stimulate a patient’s own immune system to recognize and destroy cancer cells more effectively
  • Immune checkpoint inhibitors
    • An important part of the immune system is its ability to keep itself from attacking normal cells in the body. To do this, it uses “checkpoints” — molecules on immune cells that need to be turned on (or off) (e.g., CTLA-4, PD-1) to start an immune response. Cancer cells sometimes use these checkpoints to avoid being attacked by the immune system.

• Potentially Localized Disease
  • Surgery: Removing the cancer and part of the lung
    • Pneumonectomy: Removal of a lung on one side
    • Lobectomy: Removal of a section or lobe
    • Wedge resection: Removal of part of a lobe
  • Radiation: Used when surgery is not possible or if some cancer is left behind after surgery
• Metastatic Disease
  • Chemotherapy: There are many drugs with activity, usually given in a doublet combination
    • Cisplatin, carboplatin, Taxol, Taxotere, Gemzar, Navelbine, etoposide, Alimta, Camptosar
  • Targeted therapy
    • VEGF
    • EGFR
    • ALK
  • Immunotherapy
    • Checkpoint inhibitors block PD-1

• Potentially Localized Disease
  • Primary treatment: Surgery (mastectomy) or lumpectomy + radiation are considered equally curative for localized breast cancer
  • Adjuvant chemotherapy: For women at high risk of recurrence, a combination of drugs are used, including
    • Adriamycin, Taxol or Taxotere, 5-FU, Cytoxan, Carboplatin
    • Targeted therapy can be added if HER2+: Herceptin
• Metastatic Disease
  • Many chemotherapy drugs are given in different combinations
    • Docetaxel or paclitaxel
    • Platinum agents
    • Vinorelbine
    • Capecitabine
    • Liposomal doxorubicin
    • Gemcitabine
  • Hormone Therapy
    • Many breast cancers express estrogen receptor (ER+) and/or the progesterone receptor (PR+)
    • Hormone therapy to target ER is used in the adjuvant or metastatic settings to treat breast cancer (alone or in combination with chemotherapy)
      • Drugs that block estrogen binding: Tamoxifen, Fareston, Faslodex
      • Aromatase inhibitors block estrogen production: Femara, Arimidex, Aromashin
  • Targeted Therapy
    • These are generally given in combination with chemotherapies
      • HER2+: Herceptin, Perjeta, Kadcyla, Tykerb
      • mTOR: Afinitor
      • CDK 4 and CDK6: Ibrance

• Potentially Localized Disease
  • Radical prostatectomy and external beam radiation therapy are considered to be equally curative for localized disease
  • External beam radiation +2 – 3 years of hormonal therapy (medical castration) is the therapy of choice for locally advanced disease
  • Active surveillance can be utilized for low-grade cancer
• Metastatic Disease
  • Hormonal Therapy
    • Hormonal therapy to decrease circulating testosterone (T) is first-line treatment
    • Most common hormonal therapy is with drugs that tell the brain not to stimulate T production
      • Eligard, Zoladex, Trelstar, Vantas, Firmagon
    • These can be used in combination with agents that block T binding to the androgen receptor in the cancer cell
      • Eulexin, Casodex, Nilandron
  • Second Line Treatment
    • Supra-castration hormonal agents
    • Chemotherapy
    • Bone-targeting radionuclide
    • Cancer vaccine

• Potentially Localized Disease
  • Surgery is the main treatment
    • Allows correct staging
    • Prevents future blockage of the colon
    • Prevents bleeding from the cancer
  • Radiation is rarely used to treat primary colon cancer
• If it has invaded or spread at the time of surgery
  • Chemotherapy is used in the “adjuvant” setting
  • Common regimens
    • FOLFOX: 5-FU, leucovorin, and oxaliplatin
    • CapeOx: Capecitabine and oxaliplatin
    • 5-FU and leucovorin
    • Capecitabine
  • Targeted therapies
    • Targeted agents are often added to the chemotherapy regimens
      • Targeting VEGF
      • Targeting EGFR

• Potentially Localized Disease
  • Liver transplant is the best option if possible — for small tumors (one tumor smaller than 5 cm across or two to three tumors no larger than 3 cm)
  • Surgery
  • Tumor ablation: ideally, tumors smaller than 3 cm
    • Radiofrequency ablation
    • Ethanol ablation
    • Arterial embolization
• Metastatic Disease
  • Targeted therapy
    • VEGFR (vascular endothelial growth factor receptor) and PDGFR (platelet-derived growth factor receptor): Sorafenib (Nexavar)
  • Chemotherapy
    • No systemic therapy
  • Intra-hepatic arterial therapy: floxuridine (FUDR), cisplatin, mitomycin C, and doxorubicin.

• Potentially Localized Disease
  • Surgery is the mainstay treatment
    • Often used in conjuction with chemotherapy and/or chemotherapy + radiation therapy in the newadjuvant setting
    • ECF (epirubicin, cisplatin, and 5-FU)
    • Docetaxel or paclitaxel + either 5-FU or capecitabine + radiation
    • Cisplatin + either 5-FU or capecitabine + radiation
    • Paclitaxel and carboplain + radiation
• Metastatic Disease
  • Chemotherapy
    • ECF is the most commonly used regimen
  • Targeted therapy
    • VEGF: Cyramza
    • HER2: Approximately one-fifth of stomach cancers: Herceptin

• Standard of care: Therapies that are approved by regulatory agencies — in the US, this agency is the FDA (Food and Drug Administration)
• Experimental therapies: Treatments not approved by the FDA — usually done in the setting of a clinical trial
• The vast majority of metastatic cancer cannot be cured. Clinical trials should always be considered for these patients.
  • Phase 1: Dose finding for toxicity, generally non-cancer type specific
  • Phase 2: Targeting a specific cancer at a specific dose to determine efficacy
  • Phase 3: Comparing the drug to the standard of care drug(s) to see if it is better

• The liver is a large gland that sits right below the rib cage on the right side
• The liver is unusual in that it has a double blood supply; the hepatic arteries carry oxygenated blood to the liver, and the portal vein carries venous blood from the GI tract to the liver
• It processes nutrients absorbed from the intestine
• It makes clotting factors, that allow your blood to clot if you’re cut
• It secrets bile to help the body absorb fats
• 

• Gender: Approximately twice as common in men
• Chronic viral hepatitis: Hep B or Hep C; these infections lead to cirrhosis (scarring) of the liver, which is a risk factor for liver cancer
  • Chronic Hepatitis B is the leading cause of liver cancer in Asia and Africa
    • The relative risk of developing liver cancer in Hepatitis B carrier is 100-times greater than the risk in uninfected individuals.
  • Chronic Hepatitis C is the leading cause of liver cancer in Japan, Europe, and North America
    • The relative risk of developing liver cancer in Hepatitis C carrier is 20-times greater than the risk in uninfected individuals.
  • The presence of cirrhosis increases these relative risks
• Alcohol: Leads to cirrhosis
• Hemochromatosis: Familial condition in which the body holds on to too much iron
• Aflatoxins: Fungus associated with storing grains in tropical environments
• Lifestyle: Obesity (contributes to cirrhosis), anabolic steroids, smoking

• Prevent and treat hypatitis infections
  • Hepatitis B vaccine
  • Hepatitis C treatment: Harvoni
• Avoid alcohol abuse
• Avoid smoking
• Avoid obesity

• No proven strategy
• For people at higher risk of liver cancer due to cirrhosis (from any cause) or chronic hepatitis: alpha-fetoprotein (AFP) blood tests and ultrasound exams every 6 to 12 months

• Unfortunately, we often don’t find liver cancer until it causes symptoms in the patient.
• For lesions that are greater than 1 cm in size, a triple-phase CT or MRI can be used to assess the liver and make a diagnosis in most cases.
  • Biopsy can confirm a diagnosis if imaging is unclear.
• In addition, a patient’s liver functions is graded by the Child-Pugh system.
• TNM Staging
  • T-Stage:
  • N-Stage:
  • M-Stage:
• Overall Stage:
  
• Child-Pugh Score to Assess Cirrhosis
  • Based on five factors
    • Blood levels of bilirubin
    • Blood levels of albumin
    • Prothrombin time (clotting time)
    • Presence of fluid (ascites) in the abdomen
    • Whether brain function is affected
  • Based on these factors, liver function is divided into three classes
    • Class A: All factors are normal — good operative risk
    • Class B: Mild abnormalities — moderate operative risk (there’s risk but the patient most probably will be taken to surgery)
    • Class C: Severe abnormalities — poor operative risk (generally, patient would not be taken to surgery)

• Potentially Resectable
  • Stage I and II, Child-Pugh Class A or B
  • Potential candidates for liver transplant
    • Must meet transplant criteria
  • Potential candidates for surgical resection
    • Not portal hypertension, adequate liver reserve
  • Potential candidates for locoregional therapies
• Unresectable
  • Tumor Location or Inadequate Liver Reserve
  • Potential candidates for liver transplant
    • Must meet transplant criteria
  • In non-transplant candidates, locoregional therapy is preferred
  • Systemic therapy
• Locoregional Therapies
  • Ablation
    • Ablation may be curative if T < 3 cm; can prolong survival when T > 3 cm (but < 5)
      • Radiofrequency
      • Cryoablation
      • Percutaneous alcohol ablation
      • Microwave
  • Arterial-Directed Therapies
    • Arterial-directed therapies are based on the ability to isolate an arterial blood supply to the tumor
      • Transarterial embolization with chemotherapy, drug-eluting beads, or radiotherapeutic microspheres
  • External Beam Radiation Therapy
    • Often used for patients with multiple lesions
    • Stereotactic body radiation therapy (SBRT)
    • Intensity-modulated radiation therapy (IMRT)
    • 3D conformational radiation therapy
• System Therapy
  • Sorafenic (Nexavar)
    • A “targeted” therapy
    • Tyrosine kinase inhibitor against VEGFR, PDGFR, and RAF kinases
    • Should be used only in Child-Pugh Class A
    • Increases median survival by approximately 3 months
    • It is being used in conjunction with locoregional therapy to try and increase survival
  • Clinical trials