Biology of Cancer & Tumor Spread
Stress Concepts
Objectives Lecture 2 on Cancer
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Review normal physiology to see where cancer cells differ and how cancer develops
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Define neoplasm and explain how neoplastic growth differs from the normal adaptive changes
(hypertrophy, hyperplasia, etc.)
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State ways benign and malignant neoplasms differ
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Relate cell differentiation to the behavior of the tumor
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Discuss the roles of aging and clonal expansion in the etiology of cancer
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Describe the role of gene mutation in the etiol. of ca
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Define oncogenesis and angiogenesis and explain their role in cancer cell proliferation
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Discuss viral and bacterial causes of cancer and the role of the immune system in cancer
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Discuss the relationship of the immune system and cancer
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Discuss tumor spread
Stress effects
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Describe the neurological, psychological, immunological and endocrinological aspects of stress
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Describe the physiologic and psychological effects of chronic stress response
Physiologic concepts
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Cellular reproduction (muscle cells and nerve cells don’t reproduce)
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Rates depend on cell type, need
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Control by hormones, cytokines & growth factors
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cytoplasmic signal cascade
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second messenger proteins (RAS)
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nuclear transcription factors (copies nucleas then divides)
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Receptors on cell membranes
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Physical cues – space, neighbors
Review of Concepts from Ch. 1
Growth Factors
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Cells divide only when they are told to do so by growth factors
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These cause stable cells to enter the cell cycle and divide
GROWTH FACTORS:
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Attach to receptor proteins 
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Which often work by affecting G proteins 
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Which turn on enzymes (proteins) 
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Which make second messengers (from inside the cell autocrine) 
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Which go down inside the cell and make it divide
Physiology cont.
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Tumor Suppressor Genes produce proteins to
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1) Inhibit cell growth
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2) Slow down or stop second messengers
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3) Code for important brakes acting directly on cells before they reproduce
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Rb - Master brake
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p53 – detects errors in DNA, indefinite “Pause button”
Proto-oncogenes (normal genes that stimulate cell growth and proliferation)
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Genes found in cells that stimulate  cell growth, proliferation
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produce proteins – hormones, chemicals, 2nd messengers (ras) growth signals to
nucleus
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myc genes – code for transcription factors
Proto-oncogenes
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The normal genes that code for normal proteins used in cell division
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Growth factors
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Growth factor receptors
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G proteins
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Enzymes that produce second messengers
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Genes that turn the production of these proteins on and off
Cellular Differentiation (normal)
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Role to play in cell reproduction and turnover rate
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specialization in structure & function
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turnover rate (and thus likelihood of becoming cancerous)
(Cells that don’t have much of a turn over rate have fewer chances to become
cancerous)
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Cell Recognition & Adhesion to like cells
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adhesion molecules, chemical cues, anchors
Cell Clock (must have functioning RB proteins and p53 proteins)
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Telomeres function normally
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cell crowding
Figure 9-5 Example of
Normal Differentiation
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Normally, cells differentiate multiple times
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Cancer cells - No differentiation
Telomeres and Immortality
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Body cells are not immortal and can only divide a limited number of times
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Telomeres are protective caps on each chromosome and are held in place by telomerase
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Telomeres become smaller and smaller with each cell division
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Cancer cells produce more telomerase enzymes to keep the division of cancer cells expanding
Apoptosis (Programmed Cell Death)
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Damaged or worn-out cells commit “suicide”
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Initiation phase -Turn on their own enzymes inside the cell, especially caspases
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Execution phase - Digest their own cell proteins and DNA
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Are then destroyed by white blood cells
Apoptosis Can Be Caused by:
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Extrinsic, receptor pathway
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Signaling factor attached to “death domains” of cell surface receptors
Or Intrinsic, mitochondrial pathway
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Mitochondrial damage inside the cell
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Protein p53 activated by DNA damage resulting in CELL DEATH but in half of all cells P53
is mutated causing resistance to radiation and chemo becoming cancerous.
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http://www.biooncology.com/bioonc/media/video/apoptosis/apoptosis_seq1.mp4
Classification and Nomenclature
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Benign tumors
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Named according to the tissues from which they arise, and include the suffix “-oma”
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Lipoma- tumor of fat cells
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Glioma- tumor of the supportive cells of the nervous system
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Leiomyoma- tumor of the lining of the uterus
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Chondroma-tumor of the cartilage
Malignant tumors
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Named according to the tissues from which they arise
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Malignant epithelial tumors are referred to as carcinomas
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Adenocarcinoma
Malignant connective tissue tumors are referred to as sarcomas
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Rhabdomyosarcomas
Neoplasia (new growth)
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Neoplasms proliferate to form new tissue
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They do not wait for signals from the body that the new tissue is needed
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They ignore signals to stop dividing
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They often do not mature normally (differentiate) to do the “job” the tissue is supposed to do
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They do not die off (apoptosis) to keep the number of total cells constant
Benign vs. Malignant Tumors
Grow slowly
Grow rapidly
Well-defined capsule
Not encapsulated
Not invasive
Invasive
Well differentiated
Poorly differentiated
Low mitotic index
High mitotic index
Benign Uterine Tumor
With Clearly Defined Edges
Figure 0-2 p 224
Malignant Lung Tumor Invades Surrounding Tissues
Page 224
Classification and Nomenclature
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Carcinoma in situ (CIS)
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Preinvasive epithelial malignant tumors of glandular or epithelial origin that have not
broken through the basement membrane or invaded the surrounding stroma
Pathophysiologic Concepts
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Autonomy- independence in action
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Anaplasia- regression of cells to most basic
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Loss of cell clock- becomes immortality of cells
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Nuclear and cytoplasmic derangements- doesn’t look like the neighbors
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Tumor growth rate- grow faster than normal cells. Have own inherent speed.
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Tumor Angiogenesis- allows for new blood vessel grow increasing for more tumor spread.
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Tumor Growth & Spread
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Local growth & Metastasis
Metastasis (spreading)
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detachment, invasion, dissemination & seeding
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lymph nodes, sentinel node
Theory of Carcinogenesis
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Multi-step process – decades
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cellular initiation
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individual cell mutation during replication
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isn’t identified or corrected, repaired or set to self-destruct
additional mutations
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endogenous or exogenous
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Promoters of DNA Replication errs
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smoking, UV or ionizing radiation, nitrosamines
Worst case scenario
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Mutating agent
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DNA replication error or destruction of proofreading enzymes
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tumor supressor gene deactivated
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mutation that changes a proto-oncogene to an oncogene
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cell proliferation becomes uncontrolled
Role of Risk Factors
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^ or v the likelihood of mutation
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Behavioral
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Hormonal
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Inherited
Hallmarks of Cancer
Cancer Cells
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Transformation
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Autonomy
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Cancer cell’s independence from normal cellular controls
Anaplasia
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Regression
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Pleomorphic- multi shaped
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Ectopic (away from normal) sites of hormonal production
Cancer Stem Cells
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Stem cells self-renew
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Cell divisions create new stem cells
Stem cells are pluripotent (can become anything)
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Ability to differentiate into multiple different cell types
Oncogenes
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Oncogenes are mutated proto-oncogenes
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They still code for the proteins needed for cell division
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But they might produce
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Too much of the protein
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An abnormal protein
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Protein that turns on all by itself
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Protein that is made when it is not needed
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Protein that cannot turn cell division off
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Protein that should be made by a different cell
Cancer-Causing Mutations
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Cancer is predominantly a disease of aging
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Clonal proliferation or expansion
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As a result of a mutation, a cell acquires characteristics that allow it to have selective
advantage over its neighbors
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Increased growth rate or decreased apoptosis
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Multiple mutations are required before cancer can develop
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Incidence of cancer grows dramatically with aging
Types of Mutated Genes
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Secretion of growth factors
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Increased growth factor receptors
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Signal from cell-surface receptor is mutated in the “on” position
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Mutation in the ras intracellular signaling protein allows cell growth s growth factors signally
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Inactivation of Rb tumor suppressor gene
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Activation of protein kinases that drive the cell cycle
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Mutation in the p53 gene
Angiogenesis
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Growth of new vessels
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Advanced cancers can secrete angiogenic factors (VEGF: vascular endothelial growth factor)
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VEGF and Angiogenesis movie from ResearchVEGF.com
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http://www.researchvegf.com/researchvegf/media/videos/vegffull/VEGF_Angiogenesis_Full.mp4
Angiogenesis
Telomeres and Immortality
Oncogenes and
Tumor-Suppressor Genes
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Oncogenes
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Mutant genes that in their nonmutant state direct protein synthesis and cellular growth
Tumor-suppressor genes
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Encode proteins that in their normal state negatively regulate proliferation
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Also referred to as anti-oncogenes
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Mutations here stop suppression (Rb)
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Cause over-expression of genes that prevent cell death or apoptosis
Mutation of Normal Genes
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Point mutations
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Changes in one or a few nucleotide base pairs
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Most commom form of mutation
Chromosome translocation
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A piece on one chromosome is transferred to another
Mutation of Normal Genes
Mutation of Normal Genes
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Chromosome amplification (when a small piece of chromosome is repeated over and over again)
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Duplication of a small piece of chromosome over and over
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Results in an increased expression of an oncogene
Mutation of Normal Genes
A) Single pair of N-myc
B) Amplification
Mutation of Normal Genes
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Mutation of tumor-suppressor genes
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Loss of heterozygosity (what happens to the second mutation)
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Allows unregulated cellular growth
Both chromosome copies of a gene are inactivated
Gene silencing
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Whole regions of chromosomes are shut off while the same regions in other cells
remain active
Mutation of Normal Genes
Mutation of Normal Genes
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Caretaker genes
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Encode for proteins that are involved in repairing damaged DNA
Chromosome instability
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Increased in malignant cells
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Results in chromosome loss, loss of heterozygosity, and chromosome amplification
Somatic cells v. Germline cells
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Exposure to mutagens
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If the mutation occurs in somatic cells, it is not passed to progeny
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If the mutation occurs in germline cells, it can be passed to future generations
Genetics and Cancer-Prone Families
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Mutagen exposure
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Genetic events, but NOT inherited, but because damage to individual cells
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Mutations in tumor-suppressor genes
Viruses and Cancer
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Implicated
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Hepatitis B and C viruses (HBV, HCV) (hepatitis can lead to liver cancer)
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Epstein-Barr virus (EBV)
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Kaposi’s sarcoma herpesvirus (KSHV) (more susceptible in old man)
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Human papillomavirus (HPV)
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Human T cell leukemia–lymphoma virus (HTLV)
Bacterial Cause of Cancer
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Helicobacter pylori
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Chronic infections are associated with:
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Peptic ulcer disease
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Stomach carcinoma
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Mucosa-associated lymphoid tissue lymphomas
Inflammation and Cancer
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Chronic inflammation is an important factor in the development of cancer
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Cytokine release from inflammatory cells
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Free radicals
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Mutation promotion
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Decreased response to DNA damage
Tumor Spread
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Direct invasion of contiguous organs
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Metastases to distant organs
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Known as local spread
Lymphatics and blood
Metastases by way of implantation
Phases of Tumor Spread
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Transformation
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Growth
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Local invasion
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Distant metastasis
Local Spread
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Invasion
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Cellular multiplication
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Mitotic rate vs. cellular death rate
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Mechanical pressure
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Release of lytic enzymes
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Decreased cell-to-cell adhesion
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Increased motility
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Intravasation
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Extravasation
Three-Step Theory of Invasion
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Tumor cell attachment
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Degradation or dissolution of the matrix
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Fibronectin and laminin
Enzymes
Locomotion into the matrix
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Invadopodia (pseudopodia)
Metastasis
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Spread of cancer from a primary site of origin to a distant site
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Steps
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Direct or continuous extension
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Penetration into lymphatics, blood vessels, or body cavities
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Transport into lymph or blood
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Transport to secondary sites
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Entry and growth in secondary sites
Distant Metastases
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Metastasis often occurs in the first capillary bed encountered by circulating cells
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Organ tropism
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Preferential growth of cancerous cells in certain organs
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Growth factors, chemokines, hormones, tissue-selective homing receptors, and
chemotactic factors
Clinical Manifestations of CA
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Cachexia- ematioation that is caused by a tumor consuming all resources
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Anemia- cancer damage to blood vessles and have decreased ability to create new
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Fatigue-
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Complications
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Infections
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pain
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Paraneoplastic syndrome- cancer cells produce hormones that mimic other diseases.
Tumor Markers
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Tumor cell markers (biologic markers) are substances produced by cancer cells or that are found
on plasma cell membranes, in the blood, CSF, or urine
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Hormones
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Enzymes
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Genes
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Antigens
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Antibodies
Tumor markers are used to:
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Screen and identify individuals at high risk for cancer
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Diagnose specific types of tumors
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Observe clinical course of cancer
Stress
According to Mosby’s dictionary:
“Any emotional, physical, social, economic,
or other factor that requires a response
or change.”
May be a positive or negative experience, but the element of a response or change is always a factor.
STAGES of GAS (General Adaptation Syndrome)
 ALARM STAGE
 STAGE OF RESISTANCE (ADAPTATION)
 STAGE OF EXHAUSTION
ALARM STAGE
The “fight or flight” response
(AKA: the deer in the headlights phenomenon)
Sympathetic branch of CNS activated
Pituitary gland activated
some say in females:
“tend and befriend”
Activation of SNS
1. Increased heart rate
2. Shunting of blood to brain and skeletal muscles
3. Increased blood pressure
4. Increased respiratory rate
5. Increased blood glucose levels
Resistance or Adaptation Phase
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Adrenal gland is activated and adrenal hormones are released:
Cortisol: adrenal cortex
Epinephrine: adrenal medulla
Norepinephrine: nerve endings
Stage of Exhaustion
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Compensatory mechanisms break down
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Homeostasis is not obtained
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Illness or death can occur as systems fail
Prolonged Stress
Leads to:
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Obesity, anorexia, or malnutrition
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Heart disease
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Cancer
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Depression, OCD, anxiety disorders
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Ulcers
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Hair loss
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Digestive diseases
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Skin disorders, eczema
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Suicide and substance abuse
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More frequent infections