biology of cancer and tumor spread chapter 9. first medial description :egyptian text@...
TRANSCRIPT
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
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
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
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:”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…
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
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
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
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
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)