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Nursing 404

Normal and Abnormal HumanPhysiology

Cancer

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Recall Concepts

Cell Cycle Mitosis

Cytokinesis DNA Replication

Mutation

DNA Repair Cell Growth

Growth Factors

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Learning Objectives Define neoplasia and compare to cancer.

Understand how the cell cycle is regulated and how changesto this regulation may give rise to cancer.

Describe intercellular changes that occur in cancer cells andtheir significance.

Understand the multi-step basis of cancer. Understand whatis meant by a tumor suppressor gene and an oncogene andhow they play a role in cancer. Learn the importance of DNArepair genes.

Describe the initiation-promotion-progression theory ofcarcinogenesis.

Describe invasion, angiogenesis and metastasis. Describe clinical manifestations of cancer. Compare treatment modalities for the treatment of cancer.

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Cancer Leading causes of death

Age-dependent disease Incidence is rising

Deaths mainly due to lung, breast,colorectal cancer

Distinct diseases

Common underlying features

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Benign and Malignant TumorsTissue Benign Malignant

Connective Tissue

Fibrous

Cartilage

Bone

Fat

Smooth Muscle

Striated MuscleBlood Vessels

Fibroma

Chondroma

Osteoma

Lipoma

Leiomyoma

RhabdomyomaHemangioma

Fibrosarcoma

Chondrosarcoma

Osteosarcoma

Liposarcoma

Leiomyosarcoma

RhabdomyosarcomaHemangiosarcoma

Hematopoietic

Lymphoid tissue

Plasma cells

Leukocytes

Infectious mononucleosis Lymphoma

Multiple myeloma

Leukemia

Nerve TissueNerve cell

Nerve sheath

Glial tissue

Retina

Neuroma

Neurilemmoma Neurogenic sarcoma

Glioma

Retinoblastoma

Epithelium

Squamous epithelium

Glandular epithelium

Papilloma

Adenoma

Squamous carcinoma

Adenocarcinoma

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Cancer Cells Cancer cells are not under normal growth controls,

and generally proliferate rapidly. Cancer cells are generally poorly differentiated. Many cancer cells show changes in the cell cycle. Three underlying causes of growth and maturity

abnormalities observed in cancer cells include: the ability to produce telomerase

changes in pRB that governs the cell cycle rate changes in p53 that slows the cell cycle to allow

for repair of DNA mutations before celldivision.

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Cell Growth Normal cell growth controlled by molecular

signals.

Cancer cells do not follow the normalgrowth signals of the cell. Molecular signals activated by:

Extrinsic stimulienvironmental cues

Intrinsic stimuligenetic design of cell Cancer occurs when proteins that

constitute or interpret molecular signalsare altered.

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Cell Proliferation Cancer cells have a high capacity for

proliferation.

Cell division is required for cells toproliferate. The cell cycle governs the events of cell

division.

Disruption of cell cycle is often associatedwith cancer. Cancer cells are autonomous or

independent of normal growth controls.

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Cell Differentiation Cancer cells are poorly differentiated. Differentiation is the process of cell

specialization. There is an inverse relationship between

differentiation and the ability of a cell toproliferate.

As a cell becomes fully or terminallydifferentiated, it can no longer divide. The more undifferentiated, the greater

the capacity to proliferate, and the more

malignant the cancer.

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The Cell Cycle Cells must copy their DNA (replication)

before the nucleus divides (mitosis) and

the cell divides (cytokinesis). These events form the basis of the cellcycle.

The cell cycle is broadly divided into

mitosis (followed by cytokinesis) andinterphase. Within interphase, S Phase (S = synthesis)

occurs, preceded by the G1 (G = gap) phase

and followed by G2 phase.

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TelomereLoss = Cell Death

During the S phase, DNA is being copied by DNApolymerase.

DNA polymerase cannot fully copy the informationat the ends of the chromosomes.

To prevent loss of important genetic information,the ends of the chromosomes contain telomeres.

Telomeres are repeated sequences that are not

used to make cell proteins. Over time, more and more telomeres are lost. There is an association between telomere loss and

cell death.

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Cancer Cells can make

Telomerase Cancer cells proliferate continually. Recall that loss of telomeres eventually

signals the death of a cell. One way cancer cells are able to keep

dividing is by making an enzyme calledtelomerase.

Telomerase adds new telomeres to the cellchromosomes, allowing the cell to bypassthe cell death signal.

Thus, cancer cells divide indefinitely, or

are immortalized.

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The Cell CyclepRB

Cells are normally quiescent (G0).

Cells receive a signal and enter G1.

Cells that pass R point (R = restriction)within G1 are committed to complete thecell cycle.

Passage of the R point is largely governed

by the retinoblastoma protein (pRB).

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The Cell CyclepRB

Normally pRB acts as a brake to the cell. pRBs activity is governed by

phosphorylation (adding or removing aphosphate group). Many proteins regulate the phosphorylation

state of pRB, thus regulate the cell cycle.

Disruption of pRB

leads to increased cellproliferation, seen in cancer. Mutations in pRB or proteins that govern

the phosphorylation of pRB are commonlyfound in cancer cells.

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The Cell Cyclep53 p53 is a cell protein that normally pauses

the cell cycle to allow DNA repair.

If DNA is not repaired, mutations will bepassed on to cell progeny.

If these mutations alter growth signals,cancer may result.

Mutations in p53 are associated with manytypes of cancer.

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Cancer Cell Characteristics Cancer cells exhibit altered cell growth and

differentiationuncontrolled proliferation andpoor differentiation.

Multiple mutations (transformation) are requiredfor cancer to occur.

Cancer may be referred to as a neoplasiaacollection of cells due to increased proliferation.

Benign neoplasiaconfined Malignant neoplasiainvade or spreadCancer

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Cancer Cell Characteristics Altered biochemical properties

Promote growthsecretes growth factors/hormones Promote spreadsecretes proteases

Chromosomal changes Aneuploidloss of diploid state Translocations and other rearrangements Chromosomal instability

Aberrant adherence properties Loss of contact inhibition Anchorage independence Promotes invasion and metastasis

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GeneticB

asis of Cancer Cancer is genetic, but not necessarily

inherited. Genetic means that mutation is involved. Inherited means that you inherited that

mutation from a parent. Most cancers are acquired, not inherited. Conversion of a normal cell into a cancer

cell requires multiple mutations. Additional genetic changes give rise toinvasion and metastasis properties thatallow a cancer cell to be malignant.

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Cancer Genes Mutations that give rise to cancer

generally occur in three different types of

genes. Tumor suppressor genes that normallyrestrain cell growth.

Oncogenes that normally promote growth

as protooncogenes within cells. DNA repair genes that normally correctdamage or mutations in the cellular DNA.

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Tumor Suppressor Genes Tumor Suppressor (TS) genes normally suppress

tumor formation in their normal (unmutated) form.

Usually they function to inhibit cell growth anddivision.

If these genes are mutated, the proteins theyform may not worka so called loss of function.

If the suppressor genes are not suppressing tumorformation, tumors form.

Examples include transcription factors (pRB andp53) and cell adhesion proteins (APC and DCC).

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Oncogenes Expression of oncogenes often required

for a cell to transform into a cancer cell.

Many normal cell genes (protooncogenes)may mutate to form oncogenes. Protooncogenes form growth factors,

enzymes, receptors within the cell thatgenerally promote cell growth.

Mutation in these genes (oncogenes) maylead to unregulated growth or cancer. Oncogenes may also be acquired through

infection with some viruses.

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DNAR

epair Genes DNA repair genes correct mistakes that

happen to the DNA sequence either during

DNA replication, or from environmentalexposure.

Failure to fix these mutations increasesthe likelihood that cancer will arise.

Thus, mutations in DNA repair genes areassociated with an increase in cancer.

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GeneticB

asis of Cancer A series of mutations in tumor suppressor

or oncogenes are required for cancer.

Most of these mutations are acquired. Thus, most cancer is not inherited. Inherited and acquired forms of cancer

may be simple (limited number of genesinvolved) or complex.

Most inherited forms of cancer involvechanges in tumor suppressor genes.

Classic example is retinoblastoma.

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Retinoblastoma

Retinoblastoma is a rare childhood cancer of theeye.

Development of retinoblastoma involves changes inthe tumor suppressor called pRB.

Recall that pRB is a major regulator of the cellcycle.

Retinoblastoma requires mutation in both alleles of

the pRB

gene. These mutations may be inherited or acquired. Persons born with an mutated allele predisposes

them to this form of cancer. Loss of pRB function leads to unregulated growth

or cancer.

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HNPCC Hereditary NonPolyposis Colon Cancer. This form of colon cancer arises because of

mutations in DNA repair genes. Several step-wise mutations are required in both

oncogenes and tumor suppressor genes to give riseto damaged DNA repair genes.

Damaged DNA repair genes cannot correct the

errors within newly replicated DNA. This decrease in DNA repair leads to an increasein genome instability.

This so called mutator phenotype increases thelikelihood that an individual will develop cancer.

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Acquired Forms of Cancer Most forms of cancer are acquired. Cancer requires a series of mutations in somatic

cells. These mutations usually provide growth

advantages and other characteristics of cancer. Collectively these mutations result in the

transformation of a normal cell to a cancerous one.

Genes that acquire mutations include tumorsuppressor genes, oncogenes, and DNA repairgenes.

Mutations may be point mutations or may includechromosomal rearrangements such as

translocations.

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Theories of Carcinogenesis Carcinogenesis is the process of tumor

formation.

Multiple steps involved. Tumor cells are clonal or derived from a

single progenitor cell. Tumor cell markers identify cancer and

reflect this clonality. Tumor cell markers include chromosomal

alterations or other indications of cellorigin.

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The Multistep Basis of

Cancer Cancer requires accumulation of multiple,

independent, rare mutations in a single cell.

Mutations accumulate in a stepwise manner. Carcinogenesis takes time, often many

years pass between the onset of theprocess and appearance of cancer.

Multistep nature of cancer illustrated byFamilial Adenomatous Polyposis (FAP), aform of colorectal cancer.

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Familial Adenomatous

Polyposis (FAP) Deletion of adenomatous polyposis coli

(APC) tumor suppressor gene.

Deletion of second APC allele. Mutation of ras oncogene. Loss of both alleles of deleted in colon

cancer (DCC) tumor suppressor gene.

Loss of p53 tumor suppressor gene. Additional changes lead to invasion and

metastasis.

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Gene TS ONC TS TSType

Multi-StepB

asis of Cancer

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Initiation and Promotion The initiation-promotion theory includes the

concepts of clonality and multistep changes forcancer.

Two phases for tumor development: InitiationDNA mutation, irreversible, must occur

first. Promotionstimulate cell proliferation, reversible

in early stages, must follow initiation for tumorsto form. Once initiation and promotion have given rise to

cancer cell, tumor progression occursCancer. Lung cancer.

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Invasion, Angiogenesis,

Metastasis Neoplasms characterized by

unregulated growth. To be malignant,

additional changes are required: Invasion of neighboring tissues

Angiogenesis, or formation of new

blood vessels Metastasis, or spread to new sites.

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Invasion Active process involving transfer of cancer

cell across tissue barriers.

Adhesioncancer cells adhere to basementmembrane or extracellular matrix.

Proteolysisbreakdown of extracellularbarriers.

Motilitymovement of cancer cell fromorigin to neighboring sites.

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Angiogenesis Metastasis requires access to a blood (lymph)

supply.

B

lood provides nutrients required for tumorgrowth.

Angiogenesis normally occurs in a regulatedmanner (menstruation, pregnancy, wound healing).

Growth factors promote neovascularization.

Formation of new blood vessels (angiogenesis)promotes tumor cell invasion and metastasis.

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Metastasis Metastasis involves entry of tumor cell to

blood/lymph and distribution to other body

sites where secondary tumors establish. Requires both invasion and angiogenesis. Follow general patterns (vascular drainage). Some sites favored because they provide

good environments for tumor growth. Once a cancer has metastasized, the

ability to treat that cancer is usuallylimited.

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Clinical Manifestations of

Cancer Distinct diseases with similar underlying cellular

changes. Each type of cancer has its own signs and

symptoms, but several manifestations common. Examples include:

Paincommon, more so in progressive disease Cachexiasevere form of malnutrition,

associated with anorexia, tumor necrosis factor(TNF) Declining hematopoiesisanemia often

observed, tumors in bone or bone marrowsuppression can contribute.

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Cancer Treatments Depending upon the type of cancer,

therapy utilizes three major approaches

surgery, chemotherapy, radiation. Elimination of local tumor often withsurgery or radiation.

Treatment of disseminated tumor cells

with chemotherapy. Multiple modalities often employed. Diagnosis and staging of cancer critical. Cancer may be examined histologically, and

assessed for spread.

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Tumor StagingTNM System

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Breast Cancer

Kate Brown is a 42 year-old woman who presented to theradiology department for her annual mammogram. Theresults of the procedure were questionable, and an

ultrasound exam, followed by a biopsy was performed. Theresults of the histology report indicated a positive diagnosisand indicated that the cells were positive for estrogenreceptor. She underwent breast conservation surgery andradiation treatment, and was given adjuvant chemotherapy(Tamoxifen). The patient was examined every three months

for three years to detect any return of the cancer andobserve the opposite breast for any tumor formation.Annual mammograms were scheduled thereafter, and thepatient remained free of recurrences for five years.

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Breast Cancer

What is the relationship between hormones andbreast cancer?

Is hormone exposure an initiation or promoter? What type of genes are BRCA1 and BRCA2? What role do these gene types play in cancer? Why is early detection important? Why are cancers biopsied? Why are lymph nodes

biopsied? What kind of drug is tamoxifen? Why is it

important to know the estrogen receptor status ofthe cancer cells?

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Melanoma Jane Briarson is a 42 year-old woman, who is in general

good health, and an avid sailor. During her routine annualphysical, her primary care provider (PCP) noticed a

suspicious looking mole on her back, suggestive of melanoma.Physical examination also revealed the presence of a small,hard mass in her axillary region, and a biopsy was performed.

The histology report indicated that she had malignantmelanoma and that her proximal lymph nodes were involved.Body scans indicated no metastasis to the lungs, liver, orbone. The lesion and lymph nodes were surgically removedand she was treated with chemotherapy and immune therapyto prevent the proliferation of any tumor cells that were notremoved by the surgical interventions.

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Melanoma Why has there been an increase in incidence in melanoma,

but a decline in the death rate in the last several years? What is the major cause of skin cancer and how does this fit

with Jane

s lifestyle? How would you recommend preventing skin cancer? Melanoma occurs when melanocytes, which produce melanin,

become malignant. What is the role of melanin? Detection of skin cancer requires careful attention to

changes in moles and the cardinal signs: A, B, C, D

Asymmetry, Borders, Color, Diameter. What are the significance of these? How is skin cancer diagnosed? Why is the treatment of surgery along with adjuvant

therapy implemented?