Dr. Manash K. PaulDepartment of BiologyIndian Institute of Science Education and Research Mohali; www.iisermohali.ac.in

Cancer and Therapeutics

This presentation is for teaching purpose only

Introduction Cell and Molecular Biology of Cancer Development Signal Transduction and Cell Growth Regulation Genetic Pathways Genomic Stability in Cancer Dysregulation of Cell Cycle Control Apoptosis and cancer Role of respiration and cancer Warburg effect and glucose metabolism The immune system and tumorigenesis Stem Cells and Cancer stem cells Metastasis and Angiogenesis Cancer Diagnosis and Pathology Cancer therapy Principles of Cancer Chemotherapy, Drug discovery Rational Design of Cancer Therapeutics Drug Delivery Models to study cancer The Future of Cancer Research Recent papers study and Discussions

Broad areas of Lectures on Cancer and Therapeutics

Textbook & Readings: As a general background source Alberts B. et al.,

The Molecular Biology of the Cell 4th Edition (2002) Garland Science Press, ISBN 0-8153-3218-1 is recommended. As a detailed source Robert A. Weinberg, The Biology of Cancer Garland Science Press, ISBN 0-8153-4078-8 (2007). Lauren Pecorino, Molecular Biology of Cancer, Oxford University Press. ISBN 978-0-19-921148-7 (2008). M. Molls, P. Vaupel, C. Nieder, M.S. Anscher. The impact of tumor biology on cancer treatment and multidisciplinary strategies, Springer. ISBN 978-3-540-74385-9 (2009). Yi Lu, R. I. Mahato, Pharmaceutical perspectives of cancer therapeutics, Springer. ISBN 978-1-4419-0130-9 (2009).

www.rapidcityjournal.com/.../2007/032607.html

Cancer - incurable suffering?

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Fundamental Biological aspects of Cancer

INTRODUCTION

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Cancer Statistics US Mortality, 2006

1. Heart Diseases 631,636 26.0

2. Cancer 559,888 23.1

3. Cerebrovascular diseases 137,119 5.7

4. Chronic lower respiratory diseases 124,583 5.1

5. Accidents (unintentional injuries) 121,599 5.0

6. Diabetes mellitus 72,449 3.0

7. Alzheimer disease 72,432 3.0

8. Influenza & pneumonia 56,326 2.3

Rank Cause of Death No. of deaths % of all deaths

Burden of Cancer in the World 15 million new cases of cancer by 2020 12 million deaths from cancer by 2020 Lung, stomach, liver, colon and breast cancer cause

the most cancer deathshttp://www.cancer.org/docroot/STT/STT_0.asp

www.who.int/mediacentre/factsheets/fs297/en/index.html, P. Kanavos; Annals of Oncology 17 (Supplement 8): viii15–viii23, 2006

http://www.cancer.org/docroot/STT/STT_0.asp

February 26, 2001 6

Change in US Death Rates from 1991 to 2006

17.8

63.334.8

313.0

215.1

43.6

180.7200.2

0

100

200

300

400

Heart diseases Cerebrovasculardiseases

Influenza &pneumonia

Cancer

19912006

Rate Per 100,000

Why Cancer is Potentially Dangerous?

Sources: American Cancer Society home page. 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.

2006 Mortality Data: US Mortality Data 2006, NCHS, Centers for Disease Control and Prevention, 2009.http://www.cancer.org/docroot/STT/STT_0.asp

?

2009 Estimated US Cancer Deaths

• Lung & bronchus 30%• Prostate 9%• Colon & rectum 9%• Pancreas 6%• Leukemia 4%• Liver & intrahepatic 4%

bile duct• Esophagus 4%• Urinary bladder 3% • Non-Hodgkin lymphoma 3%• Kidney & renal pelvis 3%• All other sites 25%

26% Lung & bronchus15% Breast9% Colon & rectum

6% Pancreas 5% Ovary 4% Non-Hodgkin lymphoma 3% Leukemia3% Uterine corpus

2% Liver & intrahepaticbile duct

2% Brain/ONS25% All other sites

Men292,540

Women269,800

Source: American Cancer Society home page.http://www.cancer.org/docroot/home/index.asp

Have you heard of heart cancer?

What is Cancer ? How are cancer named ?

Cancer - diseases, in which cells divide abnormally without control

and are able to invade other tissues

Most cancers are named for the organ or type of cell in which they start

http://www.cancer.org/docroot/home/index.aspSource: American Cancer Society home page.

Carcinoma - cancer of skin or in tissues that line or cover internal

organs.

Sarcoma - cancer of bone, cartilage, fat, muscle, blood vessels, or

other connective or supportive tissue.

Leukemia - cancer of blood-forming tissue such as the bone

marrow and causes large numbers of abnormal blood cells.

Lymphoma and myeloma - cancers of the cells of the immune

system.

Central nervous system cancers - cancers of the tissues of the

brain and spinal cord.

Cancer types ?

Have you heard of cancer of RBC?

Benign tumors are not cancer: Benign tumors are generally

slow growing expansive masses often with a “Pushing margin” and enclosed within a fibrous capsule.

Malignant tumors are cancer: Malignant tumors are usually rapidly growing, invading local tissue and spreading to distant sites.

Tumors ?

Benign tumor grows locally

Malignant tumor/ cancer cells can spread by invasion and metastasis

Time

Malignant and Benign tumors

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Cancer history ?

Hippocrates used the Greek words, carcinos and carcinoma to describe tumors, thus calling cancer “karkinos”

Well known to ancient Egyptians and to succeeding civilizations. The world's oldest documented case of cancer hails from ancient Egypt, in 1500 b.c.

Treated by cauterization, a method to destroy tissue with a hot instrument called "the fire drill”

Rudolph Virchow in late 19th century recognized that even cancerous cells were derived from other cells

Karl Thiersch (German): cancer spread through malignant cells

Cancer chemotherapy was started by Louis Goodman and Alfred Gilman in the 1940s with the use of nitrogen mustards

Sidney Farber tageted cancer using folic acid antagonist as drugs

The Etiology of Cancer Viruses (papilloma, Epstein-Barr, hepatitis B, retrovirus)

Radiation exposure

Environmental/ industrial carcinogens* Asbestos* Aromatic amines* Bischloromethyl ethers* Beta-naphthalene and benzedrine* Polycyclic hydrocarbons* Drug-induced cancers (alkylators such as melphalan and cyclophosphamide)* Nickel* Vinyl chloride* Isopropyl alcohol* Diet and nutrition

Tobacco and alcohol consumption

Immunodeficiency syndromes: HIV is associated with Kaposi's sarcoma,

non-Hodgkin's lymphoma

Genetic susceptibility syndromes

Origin of Cancer Cells grow and divide in a controlled way to produce more cells

The genetic material (DNA) of a cell can become damaged or changed, producing mutations that affect normal cell growth and division

Extra cells thus formed may form a mass of tissue called a tumor.

Uncontrolled growth

Cell damage - no repair

Apoptosis / programmed cell death

Normal cell

First mutation

Second mutationThird mutation

Fourth/ subsequent mutation

No Apoptosis

Normal cell division

Cancer cell division

Cell damage - no repair

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Normal cell

Formation of Cancer

Carcinogenesis Carcinogenesis: A Process by which normal cells gets transformed into

cancer cells.

Hyperplasia: Abnormal proliferation of normal cells within a tissue and may

result in the enlargement of an organ or formation of a benign tumor

Dysplasia: Condition characterized by an abnormal expansion of immature

cells within a tissue,suggestive of an early neoplastic process.

Neoplasia: Abnormal, uncoordinated proliferation of cells, usually causes a

lump or tumor. Neoplasms may be benign, pre-malignant or malignant.

Carcinogenesis

Paul Graphics

Normal Hyperplasia Mild-dysplasia Cancer (severe dysplasia) Cancer (invasive)

Clinical symptoms or signs of cancer

Cancer normally presents with certain signs or symptoms and are as follows:

Alteration in eating habit Loss of appetite Change in bowel habit The presence of a lump at any site The appearance of bleeding Unexplained recurrent pain Recurrent fever Unexplained weight loss Repeated infections which do not clear with treatment

1. Normal tissues are the source of Tumors Tumors are made up of cellsContinuity between normal and cancer tissuesUndergoes metastasis

2. Tumors arise from many specialized cell types throughout the

body

3. Tumors are monoclonal in natureMonoclonality versus Polyclonality

Nature of Cancer

Cancer occurs with different frequencies in different populations ?

When a breast cancer cell metastasizes to lung. What does it form there a lung/ breast cancer ?

Can you plan an experiment to highlight on the monoclonality vs polyclonality issue of cancer?

What percentage of cancers are inheritable?

Can cancer be caused by a bacteria? Thank you