Cancer Uglyar T.Y.. What is cancer? Caner is defined as the continuous uncontrolled growth of cells. A tumor is a any abnormal proliferation of cells.

Cancer

Uglyar 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

location• Malignant tumors are capable of invading

surrounding tissue or invading the entire body• Tumors are classified as to their cell type• Tumors 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 cells

• Neoplasm – new growth of tissue that serves no physiological function

• Tumor – clumping of neoplasmic cells• Malignant - cancerous• Benign - noncancerous• Biopsy – 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 types

• Carcinomas; constitute 90% of cancers, are cancers of epithelial cells

• Sarcomas; 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 lifestyle

• Internal Factors – hormones, immune conditions, and inherited mutations

• Theories– Cellular change/mutation theories– Carcinogens– Oncogenes/ protooncogenes

Risks For Cancer• Lifetime risk – the probability that an individual,

over the course of a lifetime, will develop cancer or die from it

• Relative risk – measure of the strength of the relationship between risk factors and a particular cancer

• Smoking – 30% of all cancer deaths, 87% of lung cancer deaths

• Obesity – 50% higher risk for breast cancer in postmenopausal women, 40% higher risk in colon cancer for men

Biological Factors• Some cancers such as breast, stomach, colon,

prostate, uterus, ovaries and lung appear to run in families

• Hodgkin’s disease and certain leukemia's show similar patterns

• University of Utah research suggests that a gene for breast cancer exists

• A rare form of eye cancer appears to be transmitted genetically from mother to child

Reproductive And Hormonal Risks For Cancer

• Pregnancy and oral contraceptives increase a woman’s chances of breast cancer

• Late menarche, early menopause, early first childbirth, having many children have been shown to reduce risk of breast cancer

Social And Psychological Factors

• Stress has been implicated in increased susceptibility to several types of cancers

• Sleep disturbances, diet, or a combination of factors may weaken the body’s immune system

Chemicals In Foods

• Sodium nitrate when ingested forms a potential carcinogen, nitrosamine

• Sodium nitrate is still used because it is effective in preventing botulism

• Pesticide and herbicide residues

Viral Factors• Herpes-related viruses may be involved in the

development of leukemia, Hodgkin’s disease, cervical cancer, and Burkitt’s lymphoma

• Epstein-Barr virus, associated with mononucleosis, may contribute to cancer

• Human papillomavirus (HPV), virus that causes genital warts, has been linked to cervical cancer

• Helicobacter pylori causes ulcers which are a major factor in the development of stomach cancer

Medical Factors• Some medical treatments actually increase a

person’s risk for cancer• Diethylstilbestrol (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 organs

• Estrogen supplementation• Chemotherapy used to treat one form of cancer

may increase risk for another type of cancer

Properties of cancer cells

Normal cells show contact inhibition

Cancer cells lack contact inhibition

Properties of cancer cellsThey keep growing

And growing

And growing

And growing

Cancer: Benign

• Benign: localized and of small size

• Cells that closely resemble, and may function, like normal cells

• May be delineated by a fibrous (Basal lamina) capsule

• Become 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 metastatic

Invade surrounding tissue and establishment of secondary areas of growth: Metastasis

Cancer : Malignant

MetastasisCarcinoma: derived from endoderm or ectoderm

Oncology• Biology of abnormal cancer cells• They have continuous or inappropriate, usually

faster growth or larger growth patterns• They have no specific morphology and often do

not resemble their parent cells = anaplastic• They do not respond to signals for apoptosis =

programmed cell death

Apoptosis• Apoptosis 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 apoptosis

Following 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 caspase• During 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:

1. Activation of initiating caspases by specific signals2. Activation of executing caspases by the initiating

caspases which can cleave inactive caspases at specific sites.

3. Degradation of essential cellular proteins by the executing caspases with their protease activity.

Capsase activation

• Comparison 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+.

DNA

p53

What does p53 do?

• Suppresses tumors in response to DNA by inducing cell cycle arrest or apoptosis

How can you inhibit gene expression?

How is p53 Activated?

1) Regulation of p53 by MDM2

P53 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 p53• Studies 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.

Oncology• Cancer grading and staging• Cancer 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 = T• involvement in lymph nodes = N • and appearance of metastasis = M• Numbers of the stage range from x = none to 3 or 4 for each letter

Is this a high grade or low grade cancer?

0%0%

1. High

2. Low

Oncology

• Types of cancer cells are named for their site of origin:

• Adenocarcinoma• Carcinoma in situ (CIS)• Squamous• Basal cell• Astrocytomas• Melanomas• Sarcomas• Lymphomas

Oncology

• Symptoms of Cancer• Cachexia – weight loss,unexplained• Anorexia• Anemia• Impaired immune response• Pain – when the cancer is large enough to

compress nerves or organs• Lymphadema – when the tumor blocks lymph or

circulatory flow• Motor or sensory deficits

Oncology• Cancer statistics• Lung cancer has annual

new cases (incidence) of 173,770 people per year: 93,110 males and 80,660 females

• Annual mortality: 160,440 per year consisting of 92,000 males and 68,510 females

Oncology

• Cancer statistics• 28% 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

Oncology• Cancer statistics

• Risks for lung cancer:

• Smoking (75-80% of cases)

• Occupational exposure

• Nutrition/Diet

• Genetic factors

Oncology• Cancer 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

Oncology• Lab tests for cancer• Ultrasounds to determine size• CT scan with contrast– the golden standard• Genetic markers – BRCA 1 and BRCA 2• Tumor markers:

CEA – general carcinogenic antigenPSA – prostate antigenCA-125 – ovarianCA-25,27 – breastHER 2 NEU – breast tissue needed

Oncology• Lab tests for cancer

• Liver function tests

• CBC with diff

• Renal function tests

• PET scan – looks for metastasis using a radioactive glucose solution

• PT, PTT, Fibrinogen, Fibrin levels

Oncology• Lab tests for cancer• Pathology slide of tumor:(Should be kept for a period of years)

• Determines type of tumor• Source of tumor• Aggression of tumor – whether fast growing,

differentiated, or non-differentiated• Used to determine tumor growth factors and

susceptibility to certain chemotherapies

Cancer treatment.

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

Modalities of treatment:

• 1-local therapy:1-local therapy:– -surgery.-surgery.– -radiation therapy.-radiation therapy.

• 2-systemic treatment:2-systemic treatment:– chemotherapy.chemotherapy.– Hormonal therapy.Hormonal therapy.– Monoclonal antibodies.Monoclonal antibodies.– Radioactive material.Radioactive material.

• 3-supportive care.3-supportive care.• 4-non-conventional therapy.4-non-conventional therapy.

Surgery:

• Surgery was the first modality used Surgery was the first modality used successfully in the treatment of cancer.successfully in the treatment of cancer.

• It is the only curative therapy for many It is the only curative therapy for many common solid tumors.common solid tumors.

• The most important determinant of a The most important determinant of a successful surgical therapy are the absence successful surgical therapy are the absence of distant metastases and no local of distant metastases and no local infiltration.infiltration.

Cont:

• Microscopic invasion of surrounding normal Microscopic invasion of surrounding normal tissue will necessitate multiple frozen section.tissue will necessitate multiple frozen section.

• Resection or sampling of regional lymph node is Resection or sampling of regional lymph node is usually indicated.usually indicated.

• Surgery may be used for palliation in patients for Surgery may be used for palliation in patients for whom cure is not possible.whom cure is not possible.

• Has significant role in cancer prevention.Has significant role in cancer prevention.– E.g familial polyposis coli.E.g familial polyposis coli.

Surgery for prevention:

• Patients with conditions that predispose Patients with conditions that predispose them to certain cancers or with genetic traitsthem to certain cancers or with genetic traitsAssociated with cancer can have normal life Associated with cancer can have normal life span with prophylactic surgery. span with prophylactic surgery.

-colectomy .-colectomy .-oophorectomy.-oophorectomy.-thyroidectomy.-thyroidectomy.-removal of premalignant skin lesion .-removal of premalignant skin lesion .

Radiation therapy:

Radiation therapy:

• Radiation therapy: is a local modality used in the Radiation therapy: is a local modality used in the treatment of cancer .treatment of cancer .

• Success depend in the difference in the radio Success depend in the difference in the radio sensitivity between the tumor and normal tissue.sensitivity between the tumor and normal tissue.

• It involves the administration of ionizing radiation It involves the administration of ionizing radiation in the form of x-ray or gamma rays to the tumor in the form of x-ray or gamma rays to the tumor site.site.

• Method of delivery: External beam(teletherapy).Method of delivery: External beam(teletherapy).Internal beam therapy(Brachytherapy). Internal beam therapy(Brachytherapy).

Cont:

• Radiation therapy is planned and performed Radiation therapy is planned and performed by a team of nurses, dosimetrists,physician by a team of nurses, dosimetrists,physician and radiation oncologist.and radiation oncologist.

• A course of radiation therapy is preceded by A course of radiation therapy is preceded by a simulation session in which low-energy a simulation session in which low-energy beam are used to produce radiograghic beam are used to produce radiograghic images that indicate the exact beam images that indicate the exact beam location. location.

Cont:

• Radiation therapy is usually delivered in Radiation therapy is usually delivered in fractionated doses such as 180 to 300 cGy per fractionated doses such as 180 to 300 cGy per day,five times a week for a total course of 5-8 day,five times a week for a total course of 5-8 weeks. weeks.

• Radiation therapy with curative intent is the main Radiation therapy with curative intent is the main treatment in limited stage Hodgkin’s disease,some treatment in limited stage Hodgkin’s disease,some NHL,limited stage ca prostate,gynecologic NHL,limited stage ca prostate,gynecologic tumors&CNS tumor .tumors&CNS tumor .

• Also can use in palliative &emergency setting.Also can use in palliative &emergency setting.

Complication of radiation:

• There is two types of toxicity ,acute and long term There is two types of toxicity ,acute and long term toxicity.toxicity.

• Systemic symptoms such as Fatigue,local skin Systemic symptoms such as Fatigue,local skin reaction,GI toxicity,oropharyngeal reaction,GI toxicity,oropharyngeal mucositis&xerostomia.myelosuppression.mucositis&xerostomia.myelosuppression.

• Long-term sequelae:may occur many months or years Long-term sequelae:may occur many months or years after radiation therapy.after radiation therapy.

• Radiation therapy is known to be Radiation therapy is known to be mutagenic,carcinogenic,and teratogen,and having mutagenic,carcinogenic,and teratogen,and having increased risk of developing both secondary leukemia increased risk of developing both secondary leukemia and solid tumor.and solid tumor.

Nuclear medicine

Radionuclides:

• For decades have been used systemically to treat For decades have been used systemically to treat malignant disorders.malignant disorders.

• They are administer by specialists in nuclear They are administer by specialists in nuclear medicine or radiation oncologist.medicine or radiation oncologist.

• Radioactive iodine:in the from of Radioactive iodine:in the from of 131131I is effective I is effective therapy for well differentiated thyroid ca therapy for well differentiated thyroid ca

• Strontium-89. Is used for the treatment of body Strontium-89. Is used for the treatment of body metastasis.it is an alkaline earth element in the metastasis.it is an alkaline earth element in the same family as calcium same family as calcium

Chemotherapy:

Chemotherapy:

• Systemic chemotherapy is the main Systemic chemotherapy is the main treatment available for disseminated treatment available for disseminated malignant diseases.malignant diseases.

• Progress in chemotherapy resulted in cure Progress in chemotherapy resulted in cure for several tumors.for several tumors.

• Chemotherapy usually require multiple Chemotherapy usually require multiple cycles.cycles.

Classification of cytotoxic drug:

• Cytotoxic agent can be roughly categorized Cytotoxic agent can be roughly categorized based on their activity in relation to the cell based on their activity in relation to the cell cycle.cycle.

phase nonspecific. phase specific

cyto toxic drug

Cont :

• What is the difference between phase specific & What is the difference between phase specific & phase non specific?…..phase non specific?…..

• Phase non-specific: Phase non-specific: – The drugs generally have a linear dose-response The drugs generally have a linear dose-response

curve(curve( the drug administration ,the the drug administration ,the the fraction of the fraction of cell killed).cell killed).

• Phase specific:Phase specific:– Above a certain dosage level,further increase in drug Above a certain dosage level,further increase in drug

doesn’t result in more cell killing.but you can play with doesn’t result in more cell killing.but you can play with duration of infusion. duration of infusion.

What are the chemotherapeutic agent?…..

Chemotherapeutic agents:

• Alkylating agents:Alkylating agents:

• Antimetabolites:Antimetabolites:

• Antitumor antibiotic:Antitumor antibiotic:

• Plant alkaloids:Plant alkaloids:

• Other agentsOther agents

• Hormonal agent:Hormonal agent:

• Immunotherapy: Immunotherapy:

Complication of Chemotherapy:

• Every chemotherapeutic will have some Every chemotherapeutic will have some deleterious side effect on normal tissue .deleterious side effect on normal tissue .

• E.G; Myelosuppression,nausea&vomiting,E.G; Myelosuppression,nausea&vomiting,

Stomatitis,and alopecia are the most Stomatitis,and alopecia are the most frequently observed side effects.frequently observed side effects.

Criteria used to describe response are:

• Complete response (complete remission)is the (complete remission)is the disappearance of all detectable malignant disease.disappearance of all detectable malignant disease.

• Partial response:is decrease by more than 50% in the :is decrease by more than 50% in the sum of the products of the perpendicular diameters of sum of the products of the perpendicular diameters of all measurable lesions.all measurable lesions.

• Stable disease:no increase in size of any lesion nor the :no increase in size of any lesion nor the appearance of any new lesions.appearance of any new lesions.

• Progressive disease:means an increase by at least 25% :means an increase by at least 25% in the sum of the products of the perpendicular in the sum of the products of the perpendicular diameters of measurable lesion or the appearance of diameters of measurable lesion or the appearance of new lesions.new lesions.

Endocrine therapy:

Endocrine therapy:

• Many hormonal antitumor agents are functional agonist or Many hormonal antitumor agents are functional agonist or antagonist of the steroid hormone family.antagonist of the steroid hormone family.

• Adrenocorticoids:Adrenocorticoids:• Antiandrogen:Antiandrogen:• Estrogen:Estrogen:• Antiestrogen:Antiestrogen:• ProgestinsProgestins• Aromatase inhibitor:Aromatase inhibitor:• Gonadotropin-releasing hormone agonists:Gonadotropin-releasing hormone agonists:• Somatostatin analogues: Somatostatin analogues:

Adrenocorticosteroid:

• Are frequently used in combination regimen for Are frequently used in combination regimen for the treatment of lymphocytic leukemia and the treatment of lymphocytic leukemia and lymphoma.lymphoma.

• They function by binding to glucocorticoid-They function by binding to glucocorticoid-specific receptors present in lymphoid cells and specific receptors present in lymphoid cells and initiate programmed cell deathinitiate programmed cell death

• They most commonly used agent are They most commonly used agent are prednisone,methylprednisone,dexamethosone. prednisone,methylprednisone,dexamethosone.

Antiandrogens:

• Flutamide :Flutamide :

Effectively blocks the binding of androgen to Effectively blocks the binding of androgen to its receptor in the periphral tissue .its receptor in the periphral tissue .

It is used in the treatment of disseminated It is used in the treatment of disseminated prostate caprostate ca

Biological therapy:

Biologic therapy:

• Immunotherapy:Immunotherapy:– CytokinesCytokines– Cellular therapy.Cellular therapy.– Tumor vaccine:Tumor vaccine:

• Hematopoietic growth factors. Hematopoietic growth factors.

Oncology• The waves of the future:• Stem Cell Research• Oncogene 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

Oncology• Stem 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

Oncology• The waves of the future:

• Cancer vaccines

• Oncology 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