2. Cellular Aberration

2. CELLULAR ABERRATIONThe Biology of Cancer

Prof. Flas Julius Flores

TERMS

Cancer – a disease process that begins when an abnormal cell is transformed by the genetic mutation of the cellular DNA

In cancer, the abnormal cell forms a clone and begins to proliferate abnormally, ignoring growth-regulating signals in the environment surrounding the cell

Hyperplasia Metaplasia Dysplasia Anaplasia Neoplasia – new growth; tumor; can be benign or

malignant; uncontrolled cell growth that follows no physiologic demand

TERMS

Benign – not malignant; an abnormal growth that is stable, treatable and generally not life-threatening

Malignant – cancerous; cells that are invasive and tend to metastasize, uncontrollable or resistant to therapy; rapidly spreading

Invasion – refers to the growth of the primary tumor into the surrounding host tissues

Metastasis – the dissemination or spread of malignant cells to distant sites by direct spread of tumor cells to body cavities or through lymphatic and blood circulation

Characteristics of Benign and Malignant Neoplasms

Characteristics Benign Malignant

Cell characteristics

Mode of growth

Rate of growth

Well-differentiated that resemble normal cells of the tissue from which the tumor originated

Tumor grows by expansion and does not infiltrate the surrounding tissues; usually encapsulated

Usually slow

Cells are undifferentiated and often bear little resemblance to the normal cells of the tissue from which they arose

Grows at the periphery and sends out processes that infiltrate and destroy the surrounding tissues

Variable and depends on level of differentiation; the more anaplastic the tumor, the faster its growth

Characteristics of Benign and Malignant Neoplasms

Characteristics Benign Malignant

Metastasis

General effects

Tumor destruction

Ability to cause death

Negative

Is usually a localized phenomenon that does not cause generalized effects unless its location interferes with vital functions

Does not usually cause tissue damage unless its location interferes with blood flow

Does not usually cause death unless its location interferes with vital functions

Gains access to the blood and lymphatic channels and metastasizes to other areas of the body

Often causes generalized effects, such as anemia, weakness, and weight loss

Often causes tissue damage as the tumor outgrows its blood supply or encroaches on blood flow to the area; may also produce substances that cause cell damage

Usually causes death unless growth can be controlled

TERMS

Carcinoma – term used for malignant tumors of epithelial in origin (bronchogenic carcinoma, invasive ductal carcinoma, endometrial carcinoma, adenocarcinoma, squamous cell carcinoma, basal cell carcinoma)

Sarcoma – term used for malignant tumors of mesenchymal/connective tissue in origin (rhabdomyosarcoma, liposarcoma, leiomyosarcoma, angiosarcoma)

Note: benign tumors usually end with the suffix “oma”, except for lymphoma, hepatoblastoma, neuroblastoma, myeloma, melanoma. These are already malignant

TERMS

Solid tumor – an abnormal mass that does not contain cyst or liquid.

Example of conditions : breast cancer, colorectal , neuroblastoma, Wilms tumor, uterine, brain, lung cancer

liquid – mass that contain liquid.Example: Lymphomas ( Hodgkin and non-

Hodgkin), leukemia

Fibroadenoma – solid tumor

Fribrocystic change, breast – cystic/liquid tumor

TERMS

Angiogenesis – the growth of new capillaries from the host tissue by the release of growth factors and enzymes such as vascular endothelial growth factor (VEGF)

Mutation – an alteration in a DNA nucleotide sequence – the order of the four bases adenine (A), cytosine (C), thymine (T), and guanine (G)

Mutations can alter both the sequence of a gene and its regulatory sites

Tumor suppressor genes – normally suppress or negatively regulate cell proliferation by encoding proteins that block the action of growth-promoting proteins

TERMS

DNA-repair genes – the “caretaker genes” – genes involved in controlling or regulating genetic instability to ensure integrity of genetic information

Oncogenes – genes that encode proteins (oncoproteins) whose action promotes cell proliferation

TUMOR SUPPRESSOR GENES

Hallmark characteristic of a mutated tumor suppressor gene is loss of function through:

1. Loss of genetic material 2. Loss of information Examples:a. APC, MEN1, p53, RB, and WT1 – affect DNA

transcriptionb. BRCA1 and BRCA2 – play roles in DNA repairc. RB, p16 and TP53 – critical for the operation

of the cell cycle, suggesting that many tumor suppressor genes act as “gatekeeper” genes

SOME EXAMPLES OF GENES IN CANCER SUSCEPTIBILITY

ALDH2 – alcohol-related cancers APC – colorectal cancer CCND1 – head and neck cancer COMT – breast cancer CYP1A1 – lung, oral, and breast cancers,

childhood leukemias GSTM1 - bladder and breast cancers; lung

cancers HRAS – breast, ovarian, lung and colorectal

cancer risk LTA – myeloma MCIR – melanoma

THEORIES AND RESEARCH MODELS OF TUMOR DEVELOPMENTKey Points of Major of Tumorgenesis

Theory Key Points

Multistep Initiation:•Stem cell becomes initiated by acquiring one or more mutations, leading to partial escape from normal homeostatic control•Genetic mutations or epigenetic events responsible•IrreversiblePromotion•Initiated cell stimulated to proliferate but not terminally differentiate•Initiated cell acquires further genetic changes required for neoplasms•Interruptible and sometimes reversibleProgression•Malignant conversion of cell•Confers autonomous growth of initiated cell•Irreversible


Theory Key Points

Mutagenic versus epigenetic

Mutagenesis•Results in qualitative or quantitative alteration information•Chronic insults produce two to three mutations in individual cells within particular tissues•These mutations initiate tumorsEpigenetic process•Chronic insults repeatedly injure and transiently excite many cells in particular tissues•These insults alter expression of genetic information at the transcriptional, translational, or posttranslational levels•Mutations are secondary events


Theory Key Points

Nature versus nurture

Oncogene and tumor suppressor gene

Stem cell versus de-differentiation

Mutagens found in the environment (nurture) must interact with DNA (germ or somatic cell) to induce mutations un genes affecting cancer progress directly (e.g., oncogenes/tumor suppressor genes) or indirectly (e.g., DNA repair genes, growth factors)Oncogenes: Do not contact inhibit; do not terminally differentiate or undergo apoptosisTumor suppressor genes: When mutated, do not stop unregulated cell growth, induce differentiate, or undergo apoptosisStem cell•Pluripotent stem cells restricted to allow a finite number of cell to only specific lineage of cell types within the organs that arise from the stem cells•Daughter (progenitor) cells of these pluripotent stem cells would give rise to terminally differentiated cells of that lineageDedifferentiation: Some progenitor cells could revert back to a pluripotent cell

Properties of Cancer

Property Characteristics of Cancer and Transformed Cells

Explanation

Cytological changes

Altered cell growth

Increased size and number of nucleoliIncreased nuclear/cytoplasmic ratioAltered cytoskeleton

Immortality

Reflects greater activity of tumor cellsLarger nucleus reflects more activity, more genetic informationChanges contribute to increased mortality and variable sizes and shapes (pleomorphism)

Normal cells senesce (ramian viable but do not divide)During a crisis, cells mature, proliferate indefinitely, become “immortal”



Explanation

Altered cell growth Immortality Telomeres (DNA segments at the ends of chromosomes) limit the number of cell doublings. Telomeres shorten with each chromosomal replication until reaching a threshold at which cells senesce. Telomere stability is critical for cancer progression. Many cancer cells contain telomerase, an enzyme that prevents telomere shortening and enables the cell to replicate indefinitely



Explanation

Altered cell growth Decreased density-dependent growth inhibition (loss of contact inhibition)

Normal cells stop growing when they contact other cells crowding from contact compromises access to nutrientsTransformed cells do not respond to physical contact and with chemical signals from neighboring cells, thereby continue to grow beyond normal limitsLoss of contact inhibition may result from a faulty restriction point



Explanation

Altered cell growth Decreased requirement for serum

Serum normally provides growth factors necessary for cell development and survivalTypically, the growth factor binds to a receptor on the cell surface, which in turn activates the intracytoplasmic portion of the receptor to send a message to the nucleus (signal transduction), where an effect on gene function occurs.



Explanation

Altered cell growth Decreased requirement for serum

Sometimes, an abnormal growth factor receptor on the surface of cancer or transformed cell can activate the signal pathway spontaneously without exposure to growth factorCancer and transformed cell lines may grow in media without serum, suggesting that they can synthesize and secrete their own growth factors (autocrine stimulation)



Explanation

Altered cell growth Loss of anchorage-dependent growth

Loss of cell cycle control

Reduced apoptosis

Cells require a substance to grow. Transformed cells do not require a solid substrateOnly tumor cells grow in soft agar (no anchorage); cell growth in soft agar is highly correlated with tumorigenicity

Cell does not progress normally through cell-cycle pathways and checkpoints

Cancer cells are less susceptible to programmed cell death



Explanation

Changes in cell membrane

New surface antigens

New or altered glycoproteins (proteins with polysaccharides)

Cancer and transformed cells exhibit new molecules on the surfaceViruses can transform and alter multiple cell-surface antigens

Transformed cells usually have profound changes in cell-surface glycoproteinsSome changes may alter cell-cell and cell-matrix adhesionsMechanism by which polysaccharides are made and attached to protiens is deranged in transformed cells



Explanation

Changes in cell membrane

New or altered glycolipids

Content and complexity of glycolipids are reduced in transformed cell membranesGlycosphingolipid interacts with receptor proteins on the surface of normal cells to inhibit their responsiveness to growth factorsTransformed cells have less and/or altered glycosphingolipids on their cell surfaces, increasing their responsiveness to growth factors. Glycosphingolipids also serve as components of surface markers involved in normal cell growth

THE CELL CYCLE

THE CELL CYCLE

A malfunction of any of these regulators of cell growth and division can result in the rapid proliferation of immature cells

In some cases these proliferating immature cells are considered cancerous (malignant)

Knowledge of the cell cycle events is used in the development of chemotherapeutic drugs, which are designed to disrupt the cancer cells during different stages of their cell cycle

CARCINOGENESIS

Three-step process1. Initiation – initiators (carcinogens), such as

chemicals, physical factors, and biologic agents escape normal enzymatic mechanisms and alter the genetic structure of the cellular DNA

2. Promotion – repeated exposure to promoting agents causes the expression of abnormal or mutant genetics information

3. Progression – the altered cells exhibit increased malignant behavior; they now have the propensity for invasion and metastasis

CARCINOGENESIS

Etiologya. Viruses and bacteriab. Physical agentsc. Chemical agentsd. Genetics and familial factorse. Dietary factors – fats, alcohol, salt-cured or

smoked meats, nitrate-containing and nitrite containing foods, red and processed meat

f. Hormonal agents – DES, OCP and prolonged progesterone therapy

DIETARY FACTORS

Alcohol increases the risk of cancers of the mouth, pharynx, larynx, esophagus, liver, colorectum, and breast

Greater consumption of vegetables and fruits is associated with decreased risk of lung, esophageal, stomach, and colorectal cancers

High caloric dietary intake is also associated with an increased cancer risk

Obesity is clearly associated with endometrial cancer, postmenopausal breast cancers, and colon, esophagus, and kidney cancers, as wells as pancreatic cancer, gallbladder, thyroid, ovary, cervix, prostate cancer, and multiple myeloma

GRADING VERSUS STAGING

Grading – identification of the type of tissue from which the tumor originated and the degree to which the tumor cells retain the functional and structural characteristics of the tissue of origin

Staging – process of determining the extent of disease, including tumor size and spread or metastasis to distant sites

TNM StagingT – primary tumorN – regional nodal metastasisM – distant metastasis

TNM CLASSIFICATION SYSTEM Primary tumor

Tx – Primary tumor cannot be assessed

T0 – No evidence of primary tumor

Tis – carcinoma in-situ

T1, T2, T3, T4 – increasing size and/or local extent of the primary tumor

Regional lymph node metastasis

Nx – Regional LN cannot be assessed

N0 – No regional LN metastasis

N1, N2, N3 – Increasing involvement of regional LN Distant metastasis

Mx – Distant metastases cannot be assessed

Mo – No distant metastases

M1 – Distant metastases

CANCER WARNING SIGNS AND SYMPTOMS C change in bowel habits sign of colorectal cancer A sore that does not heal on the skin or in the mouth

could be malignant Unusual bleeding or discharge from rectum, bladder

or vagina could be colorectal, prostate, bladder or cervical cancer

Thickening of breast tissue or a new lump in breast Indigestion or trouble swallowing cancer of the

mouth throat esophagus or stomach. Obvious changes to moles or warts could be skin

cancer Nagging cough or hoarseness that persists for four

to six weeks could be cancer of lung or throat cancer.

OTHER MANIFESTATIONS OF CANCER

Impaired immunity Hemorrhage Anemia Anorexia-cachexia syndrome Paraneoplastic syndromes – indirect effects of

cancer

a. Breast, ovarian, and renal cancers may set up ectopic parathyroid hormone sites, causing severe hypercalcemia

b. Oat cell and lung cancers may produce ectopic secretions of insulin, PTH, ADH, and ACTH

Pain

OTHER MANIFESTATIONS OF CANCER

Physical stress – when the immune system discovers a neoplasm, it tries to destroy it using the resources of the body

Psychologic stress

ROLE OF THE NURSE

caregiver advocate case manager educator change agent counselor educator epidemiologist

Education

2. Cellular Aberration