CancerUglyar T.Y.

What is cancer?Caner is defined as the continuous uncontrolled growth of cells. A tumor is a any abnormal proliferation of cells.Benign tumors stays confined to its original locationMalignant tumors are capable of invading surrounding tissue or invading the entire bodyTumors are classified as to their cell typeTumors can arise from any cell type in the body

What Is Cancer?Cancer a large group of diseases characterized by the uncontrolled growth and spread of abnormal cellsNeoplasm new growth of tissue that serves no physiological functionTumor clumping of neoplasmic cellsMalignant - cancerousBenign - noncancerousBiopsy microscopic examination of cell development

Cancer is an umbrella term covering a plethora of conditions characterized by unscheduled and uncontrolled cellular proliferation.Almost any mammalian organ and cell type can succumb to oncogenic transformation, giving rise to a bewildering array of clinical outcomes.The causes of cancer are many and varied, and include genetic predisposition, environmental influences, infectious agents and ageing. These transform normal cells into cancerous ones by derailing a wide spectrum of regulatory and downstream effector pathways. It is just this complexity that has hampered the development of effective and specific cancer therapies.Any attempt to provide a comprehensive overview of cancer-related knowledge would be futile therefore the next two lectures will focus on topics undergoing particularly rapid progress.

Cancer continued; three cancer typesCarcinomas; constitute 90% of cancers, are cancers of epithelial cellsSarcomas; are rare and consist of tumors of connective tissues (connective tissue, muscle, bone etc.)Leukemias and lymphomas; constitute 8% of tumors. Sometimes referred to as liquid tumors. Leukemias arise from blood forming cells and lymphomas arise from cells of the immune system (T and B cells).

What Causes Cancer?External Factors chemicals, radiation, viruses, and lifestyleInternal Factors hormones, immune conditions, and inherited mutationsTheoriesCellular change/mutation theoriesCarcinogensOncogenes/ protooncogenes

Risks For CancerLifetime risk the probability that an individual, over the course of a lifetime, will develop cancer or die from itRelative risk measure of the strength of the relationship between risk factors and a particular cancerSmoking 30% of all cancer deaths, 87% of lung cancer deathsObesity 50% higher risk for breast cancer in postmenopausal women, 40% higher risk in colon cancer for men

Biological FactorsSome cancers such as breast, stomach, colon, prostate, uterus, ovaries and lung appear to run in familiesHodgkins disease and certain leukemia's show similar patternsUniversity of Utah research suggests that a gene for breast cancer existsA rare form of eye cancer appears to be transmitted genetically from mother to child

Reproductive And Hormonal Risks For CancerPregnancy and oral contraceptives increase a womans chances of breast cancerLate menarche, early menopause, early first childbirth, having many children have been shown to reduce risk of breast cancer

Social And Psychological FactorsStress has been implicated in increased susceptibility to several types of cancersSleep disturbances, diet, or a combination of factors may weaken the bodys immune system

Chemicals In FoodsSodium nitrate when ingested forms a potential carcinogen, nitrosamineSodium nitrate is still used because it is effective in preventing botulismPesticide and herbicide residues

Viral FactorsHerpes-related viruses may be involved in the development of leukemia, Hodgkins disease, cervical cancer, and Burkitts lymphomaEpstein-Barr virus, associated with mononucleosis, may contribute to cancerHuman papillomavirus (HPV), virus that causes genital warts, has been linked to cervical cancerHelicobacter pylori causes ulcers which are a major factor in the development of stomach cancer

Medical FactorsSome medical treatments actually increase a persons risk for cancerDiethylstilbestrol (DES) used 1940 to 1960 to control bleeding during pregnancy, the daughters of mothers that used DES were found to have an increased risk for cancers of the reproductive organsEstrogen supplementationChemotherapy used to treat one form of cancer may increase risk for another type of cancer

Properties of cancer cellsNormal cells show contact inhibitionCancer cells lack contact inhibition

Properties of cancer cellsThey keep growing

And growing

And growing

And growing

Cancer: Benign

Benign: localized and of small sizeCells that closely resemble, and may function, like normal cellsMay be delineated by a fibrous (Basal lamina) capsuleBecome problems due to sheer bulk or due to secretions (e.g. hormones)

Malignant tumors: high rate of division, properties may vary compared to cells of origin. Most malignant cells become metastaticInvade surrounding tissue and establishment of secondary areas of growth: MetastasisCancer : Malignant

Metastasis Carcinoma: derived from endoderm or ectoderm

OncologyBiology of abnormal cancer cellsThey have continuous or inappropriate, usually faster growth or larger growth patternsThey have no specific morphology and often do not resemble their parent cells = anaplasticThey do not respond to signals for apoptosis = programmed cell death

ApoptosisApoptosis is a tightly regulated form of cell death, also called the programmed cell death. Morphologically, it is characterized by chromatin condensation and cell shrinkage in the early stage. Then the nucleus and cytoplasm fragment, forming membrane-bound apoptotic bodies which can be engulfed by phagocytes. In contrast, cells undergo another form of cell death, necrosis, swell and rupture. The released intracellular contents can damage surrounding cells and often cause inflammation.

p53 in apoptosisFollowing DNA damage, e.g. by radiation, p53 levels rise, and proliferating cells arrest in G1. This allows time for DNA repair prior to the next round of replication. This arrest is mediated by stimulation of expression of p21CIP1, the cyclin kinase inhibitor. Very high p53 levels, or susceptible cell types, e.g. lymphocytes, are triggered to undergo apoptosis. Bcl-2 acts between p53 and the caspase:

The role of caspaseDuring apoptosis, the cell is killed by a class of proteases called caspases. More than 10 caspases have been identified. Some of them (e.g., caspase 8 and 10) are involved in the initiation of apoptosis, others (caspase 3, 6, and 7) execute the death order by destroying essential proteins in the cell. The apoptotic process can be summarized as follows:Activation of initiating caspases by specific signalsActivation of executing caspases by the initiating caspases which can cleave inactive caspases at specific sites.Degradation of essential cellular proteins by the executing caspases with their protease activity.

Capsase activationComparison between active and inactive forms of caspases. Newly produced caspases are inactive. Specifically cleaved caspases will dimerize and become active.

P53 can bind to DNA!Stabilized by Zn2+.

DNAp53

What does p53 do?Suppresses tumors in response to DNA by inducing cell cycle arrest or apoptosisHow can you inhibit gene expression?

How is p53 Activated?

Regulation of p53 by MDM2P53 tumor suppressor protein can be stabilized and activated by two separate mechanisms in response to DNA-damage-induced phosphorylation.

2) p53 nuclear export is inhibited, to ensure that it is activated in response to DNA damage.

The discovery of p53Studies of SV40-transformed cells show that a 55-kDa protein is coprecipitated with the large-T antigen (Chang et al. 1979; Kress et al. 1979; Lane and Crawford 1979; Linzer and Levine 1979; Melero et al. 1979). This association was shown to be the result of an in vivo association between the two proteins (Lane and Crawford 1979). It was then postulated that this protein could be encoded by the cellular genome. (It should be kept in mind that no middle-T was found for SV40 and that the molecular weight of this protein was similar to that of polyoma middle-T antigen). Linzer and Levine (Linzer and Levine 1979) found that the 54-kDa protein was overexpressed in a wide variety of murine SV40 transformed cells, but also in uninfected embryonic carcinoma cells. A partial peptide map from this 54-kDa protein was identical among the different cell lines, but was clearly different from the peptide map of SV40 large-T antigen (Kress et al. 1979; Linzer and Levine 1979). It was then postulated that SV40 infection or transformation of mouse cells stimulates the synthesis or stability of a cellular 54-kDa protein.

OncologyCancer grading and stagingCancer is graded upon the resemblance to normal cells = G(The higher the number, the worse the grade of cancer) i.e. G1, G2, G3, G4

Staging is based upon the presence of a primary tumor = Tinvolvement in lymph nodes = N and appearance of metastasis = MNumbers of the stage range from x = none to 3 or 4 for each letter

Is this a high grade or low grade cancer?HighLow

Oncology

Types of cancer cells are named for their site of origin:AdenocarcinomaCarcinoma in situ (CIS)SquamousBasal cellAstrocytomasMelanomasSarcomasLymphomas

OncologySymptoms of CancerCachexia weight loss,unexplainedAnorexiaAnemiaImpaired immune responsePain when the cancer is large enough to compress nerves or organsLymphadema when the tumor blocks lymph or circulatory flowMotor or sensory deficits

OncologyCancer statisticsLung cancer has annual new cases (incidence) of 173,770 people per year: 93,110 males and 80,660 femalesAnnual mortality: 160,440 per year consisting of 92,000 males and 68,510 females

OncologyCancer statistics28% of all cancer deaths are due to lung cancer This is the leading cause of cancer death in both men and women

There are more deaths from lung cancer than prostate, breast, and colorectal cancers combined

OncologyCancer statisticsRisks for lung cancer:Smoking (75-80% of cases)Occupational exposureNutrition/DietGenetic factors

OncologyCancer statistics

Prostate cancer is number two cause of cancer in men

Breast Cancer is number two cause of cancer in women

Most common non-malignant or non-fatal cancer is non-melanoma type skin cancers

OncologyLab tests for cancerUltrasounds to determine sizeCT scan with contrast the golden standardGenetic markers BRCA 1 and BRCA 2Tumor markers:CEA general carcinogenic antigenPSA prostate antigenCA-125 ovarianCA-25,27 breastHER 2 NEU breast tissue needed

OncologyLab tests for cancerLiver function testsCBC with diffRenal function testsPET scan looks for metastasis using a radioactive glucose solutionPT, PTT, Fibrinogen, Fibrin levels

OncologyLab tests for cancerPathology slide of tumor:(Should be kept for a period of years)

Determines type of tumorSource of tumorAggression of tumor whether fast growing, differentiated, or non-differentiatedUsed to determine tumor growth factors and susceptibility to certain chemotherapies

Cancer treatment.By Dr.Huda abd-alkarim.Assistant prof.& consultant oncologist.

Modalities of treatment:1-local therapy:-surgery.-radiation therapy.2-systemic treatment:chemotherapy.Hormonal therapy.Monoclonal antibodies.Radioactive material.3-supportive care.4-non-conventional therapy.

Surgery:Surgery was the first modality used successfully in the treatment of cancer.It is the only curative therapy for many common solid tumors.The most important determinant of a successful surgical therapy are the absence of distant metastases and no local infiltration.

Cont:Microscopic invasion of surrounding normal tissue will necessitate multiple frozen section.Resection or sampling of regional lymph node is usually indicated.Surgery may be used for palliation in patients for whom cure is not possible.Has significant role in cancer prevention.E.g familial polyposis coli.

Surgery for prevention:Patients with conditions that predispose them to certain cancers or with genetic traitsAssociated with cancer can have normal life span with prophylactic surgery. -colectomy .-oophorectomy.-thyroidectomy.-removal of premalignant skin lesion .

Radiation therapy:

Radiation therapy:Radiation therapy: is a local modality used in the treatment of cancer .Success depend in the difference in the radio sensitivity between the tumor and normal tissue.It involves the administration of ionizing radiation in the form of x-ray or gamma rays to the tumor site.Method of delivery: External beam(teletherapy).Internal beam therapy(Brachytherapy).

Cont:Radiation therapy is planned and performed by a team of nurses, dosimetrists,physician and radiation oncologist.A course of radiation therapy is preceded by a simulation session in which low-energy beam are used to produce radiograghic images that indicate the exact beam location.

Cont:Radiation therapy is usually delivered in fractionated doses such as 180 to 300 cGy per day,five times a week for a total course of 5-8 weeks. Radiation therapy with curative intent is the main treatment in limited stage Hodgkins disease,some NHL,limited stage ca prostate,gynecologic tumors&CNS tumor .Also can use in palliative &emergency setting.

Complication of radiation:There is two types of toxicity ,acute and long term toxicity.Systemic symptoms such as Fatigue,local skin reaction,GI toxicity,oropharyngeal mucositis&xerostomia.myelosuppression.Long-term sequelae:may occur many months or years after radiation therapy.Radiation therapy is known to be mutagenic,carcinogenic,and teratogen,and having increased risk of developing both secondary leukemia and solid tumor.

Nuclear medicine

Radionuclides:For decades have been used systemically to treat malignant disorders.They are administer by specialists in nuclear medicine or radiation oncologist.Radioactive iodine:in the from of 131I is effective therapy for well differentiated thyroid ca Strontium-89. Is used for the treatment of body metastasis.it is an alkaline earth element in the same family as calcium

Chemotherapy:

Chemotherapy:Systemic chemotherapy is the main treatment available for disseminated malignant diseases.Progress in chemotherapy resulted in cure for several tumors.Chemotherapy usually require multiple cycles.

Classification of cytotoxic drug:Cytotoxic agent can be roughly categorized based on their activity in relation to the cell cycle.

Cont :What is the difference between phase specific & phase non specific?..Phase non-specific: The drugs generally have a linear dose-response curve( the drug administration ,the the fraction of cell killed).Phase specific:Above a certain dosage level,further increase in drug doesnt result in more cell killing.but you can play with duration of infusion.

What are the chemotherapeutic agent?..

Chemotherapeutic agents:Alkylating agents:Antimetabolites:Antitumor antibiotic:Plant alkaloids:Other agentsHormonal agent:Immunotherapy:

Complication of Chemotherapy:Every chemotherapeutic will have some deleterious side effect on normal tissue .E.G; Myelosuppression,nausea&vomiting,Stomatitis,and alopecia are the most frequently observed side effects.

Criteria used to describe response are:Complete response (complete remission)is the disappearance of all detectable malignant disease.Partial response:is decrease by more than 50% in the sum of the products of the perpendicular diameters of all measurable lesions.Stable disease:no increase in size of any lesion nor the appearance of any new lesions.Progressive disease:means an increase by at least 25% in the sum of the products of the perpendicular diameters of measurable lesion or the appearance of new lesions.

Endocrine therapy:

Endocrine therapy: Many hormonal antitumor agents are functional agonist or antagonist of the steroid hormone family.Adrenocorticoids:Antiandrogen:Estrogen:Antiestrogen:ProgestinsAromatase inhibitor:Gonadotropin-releasing hormone agonists:Somatostatin analogues:

Adrenocorticosteroid:Are frequently used in combination regimen for the treatment of lymphocytic leukemia and lymphoma.They function by binding to glucocorticoid-specific receptors present in lymphoid cells and initiate programmed cell deathThey most commonly used agent are prednisone,methylprednisone,dexamethosone.

Antiandrogens:Flutamide :Effectively blocks the binding of androgen to its receptor in the periphral tissue .It is used in the treatment of disseminated prostate ca

Biological therapy:

Biologic therapy:Immunotherapy:CytokinesCellular therapy.Tumor vaccine:

Hematopoietic growth factors.

OncologyThe waves of the future:Stem Cell ResearchOncogene therapy now that cancer cells are being genetically tagged, we can tell which growth factors are present, and which enzymes turn off the gene. Soon all gene markers will have a pill that matches the enzyme, i.e. IRESSA is a tyramine kinase inhibitor, and stops the tumors growth that use tyramine kinase

OncologyStem Cell Induction there are new drugs out for stem cell induction to immunosuppress the patient, even in deadly cancers, i.e. Multiple Myeloma. Recently, the combination of lenalidomide(Revalamid), bortezomib (Velcade) and dexamethasone produced a 98% response rate in patients

OncologyThe waves of the future: Cancer vaccinesOncology is the science of cancer and treatment of all cancer patients. It is one of the most demanding and rewarding fields in medicine. The future is open for a cure.

Oncology