BIOLOGY OF CANCER AND TUMOR SPREAD Chapter 9. First Medial Description :Egyptian Text@ 2500BC-Imhotep.

BIOLOGY OF CANCER AND TUMOR SPREAD

Chapter 9

First Medial Description :Egyptian Text@ 2500BC-Imhotep

Mastectomy: Johannes Scultetus (1595-1645)-fire, acid, leather binding

Tumor – 1922

“it is tissue overgrowth that is independent of the laws governing the remainder of the body”

“neoplastic overgrowth serves no useful purpose to the organism”

Cancer

Modern: “uncontrolled clonal proliferation of cells that can arise from virtually any cell type in the body”

Derived from the Greek word for crab karkinoma – Hippocrates (460 – 370 BC)

Malignant tumors Tumor

Also referred to as a neoplasm – new growth

Clonal Proliferation of a Single Cell“Storm Troopers: Star Wars”

Benign vs. Malignant Tumors

BenignBenign MalignantMalignant

Grow slowlyGrow slowly Grow rapidlyGrow rapidly

Well-defined capsuleWell-defined capsule Not encapsulatedNot encapsulated

Not invasiveNot invasive InvasiveInvasive

Well differentiatedWell differentiated Poorly differentiatedPoorly differentiated

Low mitotic indexLow mitotic index High mitotic indexHigh mitotic index

Do not metastasizeDo not metastasize Can spread distantly Can spread distantly (metastasis)(metastasis)

Classification & Nomenclature

Benign Named according to the tissue from which they arise, and includes the suffix - “oma”LipomaGliomaLeiomyomaChondroma

Classification & Nomenclature

• Malignant tumors– Named according to the cell type

from which they arise– Epithelial tissue – carcinoma– Ductal or glandular epithelium –

adenocarcinoma Example: mammary adenocarcinoma

– Connective tissue – sarcoma Example: rhabdomyosarcoma

– Lymphatics – lymphomas– Blood forming cells – leukemia

Classification & Nomenclature

Carcinoma in situ (CIS) Preinvasive epithelial malignant tumors of

glandular or squamous cell origin that have not broken

through the basement membrane or invaded the surround stroma

Cervix, skin, oral cavity, esophagus and bronchus (epithelium)

Stomach, endometrium, breast, large bowel (glandular)

Stages of Cancer Spread

“important component to diagnosis and treatment”

Physical findings Laboratory tests –

histological/biochemical/genetic Imaging studies

Breast Cancer

Cancer Cells

Transformation Autonomy

Cancer cells: independent from normal cellular controls

AnaplasiaLoss of differentiation (specialization and organization)

“without form” - pleomorphic

Cancer and Stem Cells

Stem cells self-renew Cell divisions create new stem cells

Stem cells are pluripotent Ability to differentiate into multiple

different cell types

Stem Cell

Cancer…a genetic disease DNA RNA

Proteins(workhorse of the cell) “normal regulated growth”

DNA** RNA** Proteins** 1. Plasma membrane ** 2. Intracellular enzyme system** 3. Hormones/Growth factors**“unregulated growth…colonal proliferation** multiple mutations- how many?

Cancer…a genetic disease DNA** RNA**

Proteins**(antigen) Example:

EarlyCDT-Lung (Oncoimmune)-blood test 6 cancer associated antigens (p53, +5) Autoantibodies…against abnormal proteins**

Medscape Medical News Sept 20,2010

Tumor Markers (DNA…RNA…Proteins)

Tumor cell markers (biologic markers) are substances produced by cancer cells or that are found on tumor plasma cell membranes, in the blood, CSF, or urine Hormones Enzymes Genes Antigens Antibodies

Tumor Markers Table 9-2

Used Screen and identify individuals at high risk for cancer(CA-125, PSA, CEA, Bense Jones protein)

Diagnose specific types of tumors

Observe clinical course of cancer

Types of Genetic Lesions in Cancer Point mutation Subtle alterations (insertions,

deletions, translocation) Chromosome changes (aneuploidy

and loss of heterozygosity)

Amplification Gene silencing Exogenous sequences (tumor viruses)

Genetic Basis of Cancer

Cancer-causing mutations Disease of aging (more mutation over

time) Clonal proliferation or expansion

Mutation leads to a DarwinianSurvival advantage(↑ growth or ↓ apoptosis)

Multiple mutations are required before cancer can develop (how many?)

Oncogenes and Tumor-Suppressor Genes

Proto-oncogene/Oncogenes Mutant genes that in their non-mutant state

direct protein synthesis and cellular growth (acceleration-pedal to the metal)

Tumor-suppressor genes Encoded proteins that in their normal state

negatively regulate proliferation Also referred to as antioncogenes (put the

brakes on)

Types of Mutated Gene:” 7 mechanisms”

Secretion of growth factors (autocrine stimulation)

Increased growth factor receptors (HER2/neu)

Signal from cell-surface receptors is mutated to the “on” position

Mutation in the ras intracellular signaling protein – (cell growth without growth factors) : “kinase”

“all lead to increase growth”

Types of Mutated Genes

Types of Mutated Genes:”7 mechanisms”

Inactivation of Rb tumor suppressor(tumor suppression) inherited

Activation of protein kinase* that drive the cell cycle (oncogene)

Mutation in the p53 gene (# apoptosis)-tumor suppression gene 17p13.1

*-PO4: activates and amplifies enzymatic processes over and over…

Types of Mutated Genes:Bowel Cancer

Question: How many mutations does it take to cause cancer? “Cancer Genome Atlas”-breast

cancer 127 mutations Driver mutations: 11-15

(average=13)-directly cause growth and survival of the cancer; hit oncogenes/tumor suppression genes; limited number exist

Bystander/passenger mutations: accidental copying of DNA; no impact on the biology of cancer

Driver Mutations

“Core metabolic pathway leads to dysregulation of any tumor” One or more proto-oncogene/tumor

suppression gene may skip mutation, but others mutations activate the core pathway

CANCER

Angiogenesis (core pathway)

Growth of new blood vessels Advanced cancers can secrete

angiogenic factors (VEGF)

Telomeres and Immortality: core

Body cells are not immortal and can only divide a limited number of times (double about 50 times -Hayflick Limit: 1961)

Telomeres are protective cap on each chromosome and are held in place by telomerase (germ cells & stem cells) enzyme

Telomeres become smaller and smaller with each cell division- “somatic cells” – quit dividing/die

Telomerase enzyme: rebuilds telomeres Nobel Prize 2009:Blackburn, Greider, Szostak

Telomeres and Immortality

Mutations of Normal Genes → Cancer Genes

Point mutation (most common) Change of one or a few nucleotide base

pairs ras gene (pancreatic, colon)

Chromosome translocation A piece on one chromosome is transferred to

another t(8;14) Burkitt Lymphoma t(9;22) chronic myeloid leukemia

(Philadelphia chromosome – 1960)

Mutations of Normal Genes → Cancer Genes

Chromosome amplification Duplication of a small piece of

chromosome (DNA) over and over Result in ↑ expression of an

oncogene N-myc oncogene @ 25%

amplification

Mutation of Normal Genes

Oncogenes and Tumor-Suppressor Genes

Oncogenes Mutant genes that in their non-mutant state

direct protein synthesis and cellular growth (jammed acceleration)

Tumor-suppressor genes Encoded proteins that in their normal state

negatively regulate proliferation Also referred to as antioncogenes (put the

brakes on)

Mutations of Normal Genes →Cancer Genes

Tumor-suppression genes(“inherited”) Unregulated cellular growth (put on the brakes) Rb

gene (inactivated) → retinoblastoma, lung, breast, bone

Two hits or mutations to inactivate the genes(Rb) Childhood retinoblastomas: 2 forms-inherited(2-6

mo.)/sporadic(2-4 yrs) De Gouvea(1872)-Brazilian Ophthmol. :young boy & his

2 daughters= cancer can be inherited

Mutations of Normal Genes → Cancer Genes

Loss of heterozygosity Loss of a chromosome region in one

chromosome Unmasks mutation in the other locus of a

tumor suppression gene

Mutation of Normal Genes: Tumor Suppression Genes

Mutations of Normal Genes → Cancer Genes

Gene silencing No mutation or change in DNA

sequence Whole regions of chromosomes are shut off while the same regions in other cells remain active

Shuts off critical tumor suppression genes

Mutations of Normal Genes → Cancer Genes

Caretaker genes(“inherited”) Encode for proteins that are involved in

repairing damaged DNA (UV or ionizing radiation, chemicals and drugs)

Loss lead to increase mutation rates Chromosome instability

Increase in malignant cells Results in chromosome loss, loss of

heterozygosity and chromosome amplificationLoss of tumor suppression genes with

overexpression of oncogenes

Genetics and Cancer-Prone Families

Somatic cells – most cancers Exposure to mutagen Defect in DNA repair Not inherited

Germ line cells (sperms and eggs) Vertical transmission of cancer causing genes Tumor suppression and caretaker genes One mutant allele (mom or dad), loss of

heterozygosity in some cells → tumors

Viruses and Cancer

Implicated Hepatitis B & C viruses* Epstein-Barr Virus (EBV) Kaposi’s Sarcoma Herpes Virus (KSHV) Human Papillomavirus (HPV)* Human T cell Leukemia – Lymphoma

Virus (HTLV)

*80% virus-linked cancers

Bacterial Causes of Cancer

Helicobacter pylori Chronic infections associated with:

Peptic ulcer diseaseStomach carcinomaMucosa-associated lymphoid tissue lymphoma

Immunity and Cancer

Surveillance – “nonself” Viral-induced cancers

Immune defect – HIV /immunosuppressants ↑ viral cancers

Organ transplant – immunosuppression – little or no ↑ in prevalent cancers

So → ?

Immunity and Cancer

Chronic inflammation – “complex” Cytokine release form inflammatory cells –

may promote growth Free radicals Mutation promotion ↓ response to DNA damage

Diseases Ulcerative colitis – 30x ↑ Liver – HBV/HBC - ↑ risk Lung cancer – chronic asthma ↑66%

Cancer Progression and Metastasis

Metastasis – “a defining characteristic of cancer” Localized may be cured(“in situ”)

Breast : 5 year survival > 90% - local5 year survival < 3% -

metastatic Pattern of spread

Vascular, lymphatic and natural tissue planes Selectivity

Breast to bone, not kidney or spleen Lymphomas to spleen, not bone

Distant Metastasis

Cancer cells must detach(invade) and migrate from its primary location

Survive passage through the body Attach, invade and multiply while

stimulating angiogenesis Thus:

#1. Vast majority of cancer cells do not have the

ability to form metastasis“appropriate cancer “seed” and a permissive

“soil”

Therapy for Cancer

Surgery (1800-1900s) Halsted Radical vs simple mastectomy vs local

excision + radiation Chemotherapy 3 to 7 drugs (ALL)

Bone marrow transplant-maximum chemotherapy

Radiation to tumors(Hodgkin’s lymphoma) Targeted: mutated gene’s protein

Breast cancer +Her-2 membrane receptor: antibody:Herceptin

CML: kinase signal inhibitor: Gleevec

Why do the cancer cells becomeresistant to chemo/targeted therapy? A few stem cells of the cancer

mutate and produce a new protein product that specific chemo/targeted therapy can no longer inhibit and kill.

A new generation of resistant cancer cells evolves

Clinical Manifestations of Cancer• Pain

– Little or no pain is associated with early stages of malignancy

– Influenced by fear, anxiety, sleep loss, fatigue and overall physical deterioration

– Mechanism• Pressure, obstruction, invasion of sensitive

structures, stretching of visceral surfaces, tissue destruction and inflammation

– Priorities of treatment1.Control – rapid and complete (patient)2.Prevention – of recurrence

Clinical Manifestations of Cancer Fatigue

Tiredness, weakness, lack of energy, exhaustion, lethargy, inability to concentrate, depression, sleepiness, boredom, lack of motivation and ↓ mental status

Most frequently reported symptom – cancer/treatment

Mechanism – poorly understood

Clinical Manifestations of Cancer • Cachexia

– Most severe form of malnutrition– Present in 80% of cancer patients at death– Includes

• Anorexia, early satiety, weight loss, anemia asthenia, taste alterations and altered protein, lipid and carbohydrate metabolism

– Mechanism – multifactoral• Hormones (leptin)• Neuropeptides• Pro-inflammatory cytokines

Cachexia

Clinical Manifestations of Cancer Anemia

Decreased amount of hemoglobin in the blood

MechanismsChronic bleeding resulting in Fe

deficiency, severe malnutrition, medial therapies or malignancy in blood forming organs

Suppression of erythropoietin on the bone marrow

rHuEPO

Clinical Manifestations of Cancer Leukopenia and thrombocytopenia

Direct tumor invasion to the bone marrow Chemotherapy toxic to bone marrow

Infection Risk increases when the absolute neutrophil

and lymphocyte counts fall ANC = WBC x (% neurophils + % bands), if < 1000 protective → isolation)

[Table 10-3 Review]

Clinical Manifestations of Cancer Paraneoplastic syndromes

Symptom complex unexplained by local or distant spread of the tumor or by the effects of hormones released by the tissues from which the tumor arose

10% of individuals Earliest symptoms of an unknown cause May represent serious and life threatening

problems May mimic cancer progression and interfere

with appropriate treatment.[Table 10-4] Review

Side Effects of Cancer Treatment“targeting the most rapidly growing cells” Gastrointestinal tract

Oral ulcers, malabsorption and diarrhea Nausea and vomiting → antiemetic therapy Supplemental nutrition (enteral or

parenteral) Bone marrow

Anemia – ↓RBC with fatigue Platelets – bleeding White blood cells – infection (ANC)