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This presentation is for teaching purpose only




             Cancer and Therapeutics




Dr. Manash K. Paul
Department of Biology
Indian Institute of Science Education and Research
Mohali; www.iisermohali.ac.in
Broad areas of Lectures on Cancer and Therapeutics
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                               www.rapidcityjournal.com/.../2007/032607.html
Metastasis and Angiogenesis
Cancer Diagnosis and Pathology                                        Textbook & Readings:
                                                        As a general background source Alberts B. et al.,
Cancer therapy                                    The Molecular Biology of the Cell 4th Edition (2002)
                                                  Garland Science Press, ISBN 0-8153-3218-1 is
Principles of Cancer Chemotherapy, Drug discovery recommended. As a detailed source Robert A. Weinberg,
                                                  The Biology of Cancer Garland Science Press, ISBN
Rational Design of Cancer Therapeutics            0-8153-4078-8 (2007). Lauren Pecorino, Molecular
                                                  Biology of Cancer, Oxford University Press. ISBN
Drug Delivery                                     978-0-19-921148-7 (2008). M. Molls, P. Vaupel, C.
                                                  Nieder, M.S. Anscher. The impact of tumor biology on
Models to study cancer                            cancer treatment and multidisciplinary strategies,
The Future of Cancer Research                     Springer. ISBN 978-3-540-74385-9 (2009). Yi Lu, R. I.
                                                  Mahato, Pharmaceutical perspectives of cancer
Recent papers study and Discussions               therapeutics, Springer. ISBN 978-1-4419-0130-9 (2009).
Cancer - incurable
www.dylanmatthews.com/images/cancer.jpg
                                                       suffering?




meddean.luc.edu/lumen/MedEd/.../MELTON/TITLE.HTM             topnews.in/health/files/mouth_cancer_0.jpg        hypnotiqueolmecpunch.org/Strangewomen_1.htm




                                                                                                   students.umf.maine.edu/~delanonh/negative.html
      myhealth.gov.my/.../adult/Breast_Cancer.gif   taconichills.k12.ny.us/.../lungcancerpic.jpg                                            meddean.luc.edu/lumen/MedEd/.../MELTON/TITLE.HTM
INTRODUCTION


                                                                    Fundamental Biological aspects
                                                                    of Cancer




                                                                http://southerngent.files.wordpress.com/2009/06/beat-breast-cancer.jpg




http://www.naturalhealthlibrarian.com/images/ebook_cancer.jpg     http://media.merchantcircle.com/25810987/help%20key_medium.jpeg
Cancer Statistics
US Mortality, 2006
      Rank     Cause of Death                                No. of deaths % of all deaths

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


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
                                                                                             http://www.cancer.org/docroot/STT/STT_0.asp
the most cancer deaths                                www.who.int/mediacentre/factsheets/fs297/en/index.html, P.
                                                      Kanavos; Annals of Oncology 17 (Supplement 8): viii15–viii23, 2006
Change in US Death Rates from 1991 to 2006

     400
                     Rate Per 100,000
                                                                                                               1991
                313.0
                                                                                                               2006
     300


                                                                                                       215.1       ?
                            200.2
     200                                                                                                        180.7




     100
                                              63.3
                                                         43.6             34.8
                                                                                     17.8
        0
               Heart diseases             Cerebrovascular                 Influenza &                    Cancer
                                             diseases                     pneumonia


                         Why Cancer is Potentially Dangerous?

Sources: American Cancer Society home page. 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.
   February 26, 2001                                                                                                    6
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

                                                     Men      Women
                                                    292,540   269,800

•     Lung & bronchus       30%                                         26%   Lung & bronchus
•     Prostate               9%                                         15%   Breast
•     Colon & rectum         9%                                          9%   Colon & rectum
•     Pancreas               6%                                          6%   Pancreas
•     Leukemia               4%                                          5%   Ovary
•     Liver & intrahepatic   4%                                          4%   Non-Hodgkin lymphoma
      bile duct                                                          3%   Leukemia
•     Esophagus              4%                                          3%   Uterine corpus
•     Urinary bladder        3%                                          2%   Liver & intrahepatic
•     Non-Hodgkin lymphoma 3%                                                 bile duct
•     Kidney & renal pelvis  3%                                          2%   Brain/ONS
•     All other sites       25%                                         25%   All other sites




    Have you heard of heart cancer?

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




                        Source: American Cancer Society home page.
                          http://www.cancer.org/docroot/home/index.asp
Cancer types ?
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.        Have you heard of cancer of RBC?
Tumors ?
   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.
                         Malignant and Benign tumors
                  Benign tumor Malignant tumor/ cancer cells can
                  grows locally spread by invasion and metastasis




              Time
                                                          Paul Graphics
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.

                                       Formation of Cancer
             Normal cell                                               Normal cell division




                                                              Apoptosis / programmed
                                                              cell death
                             Cell damage - no repair
                                                                       Cancer cell division

                                               Cell damage - no repair

             Normal cell                                                 No Apoptosis

                      First mutation

                                Second mutation
                                            Third mutation

                                                       Fourth/ subsequent
             Paul Graphics                                  mutation     Uncontrolled growth
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

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




           Paul Graphics
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
Nature of Cancer
1.     Normal tissues are the source of Tumors
        Tumors are made up of cells
        Continuity between normal and cancer tissues
        Undergoes metastasis

2.     Tumors arise from many specialized cell types throughout the
       body

3.     Tumors are monoclonal in nature
        Monoclonality versus Polyclonality
     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

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Cancer Introduction Class

  • 1. This presentation is for teaching purpose only Cancer and Therapeutics Dr. Manash K. Paul Department of Biology Indian Institute of Science Education and Research Mohali; www.iisermohali.ac.in
  • 2. Broad areas of Lectures on Cancer and Therapeutics 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 www.rapidcityjournal.com/.../2007/032607.html Metastasis and Angiogenesis Cancer Diagnosis and Pathology Textbook & Readings: As a general background source Alberts B. et al., Cancer therapy The Molecular Biology of the Cell 4th Edition (2002) Garland Science Press, ISBN 0-8153-3218-1 is Principles of Cancer Chemotherapy, Drug discovery recommended. As a detailed source Robert A. Weinberg, The Biology of Cancer Garland Science Press, ISBN Rational Design of Cancer Therapeutics 0-8153-4078-8 (2007). Lauren Pecorino, Molecular Biology of Cancer, Oxford University Press. ISBN Drug Delivery 978-0-19-921148-7 (2008). M. Molls, P. Vaupel, C. Nieder, M.S. Anscher. The impact of tumor biology on Models to study cancer cancer treatment and multidisciplinary strategies, The Future of Cancer Research Springer. ISBN 978-3-540-74385-9 (2009). Yi Lu, R. I. Mahato, Pharmaceutical perspectives of cancer Recent papers study and Discussions therapeutics, Springer. ISBN 978-1-4419-0130-9 (2009).
  • 3. Cancer - incurable www.dylanmatthews.com/images/cancer.jpg suffering? meddean.luc.edu/lumen/MedEd/.../MELTON/TITLE.HTM topnews.in/health/files/mouth_cancer_0.jpg hypnotiqueolmecpunch.org/Strangewomen_1.htm students.umf.maine.edu/~delanonh/negative.html myhealth.gov.my/.../adult/Breast_Cancer.gif taconichills.k12.ny.us/.../lungcancerpic.jpg meddean.luc.edu/lumen/MedEd/.../MELTON/TITLE.HTM
  • 4. INTRODUCTION Fundamental Biological aspects of Cancer http://southerngent.files.wordpress.com/2009/06/beat-breast-cancer.jpg http://www.naturalhealthlibrarian.com/images/ebook_cancer.jpg http://media.merchantcircle.com/25810987/help%20key_medium.jpeg
  • 5. Cancer Statistics US Mortality, 2006 Rank Cause of Death No. of deaths % of all deaths 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 http://www.cancer.org/docroot/STT/STT_0.asp 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 http://www.cancer.org/docroot/STT/STT_0.asp the most cancer deaths www.who.int/mediacentre/factsheets/fs297/en/index.html, P. Kanavos; Annals of Oncology 17 (Supplement 8): viii15–viii23, 2006
  • 6. Change in US Death Rates from 1991 to 2006 400 Rate Per 100,000 1991 313.0 2006 300 215.1 ? 200.2 200 180.7 100 63.3 43.6 34.8 17.8 0 Heart diseases Cerebrovascular Influenza & Cancer diseases pneumonia Why Cancer is Potentially Dangerous? Sources: American Cancer Society home page. 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. February 26, 2001 6 2006 Mortality Data: US Mortality Data 2006, NCHS, Centers for Disease Control and Prevention, 2009. http://www.cancer.org/docroot/STT/STT_0.asp
  • 7. 2009 Estimated US Cancer Deaths Men Women 292,540 269,800 • Lung & bronchus 30% 26% Lung & bronchus • Prostate 9% 15% Breast • Colon & rectum 9% 9% Colon & rectum • Pancreas 6% 6% Pancreas • Leukemia 4% 5% Ovary • Liver & intrahepatic 4% 4% Non-Hodgkin lymphoma bile duct 3% Leukemia • Esophagus 4% 3% Uterine corpus • Urinary bladder 3% 2% Liver & intrahepatic • Non-Hodgkin lymphoma 3% bile duct • Kidney & renal pelvis 3% 2% Brain/ONS • All other sites 25% 25% All other sites Have you heard of heart cancer? Source: American Cancer Society home page. http://www.cancer.org/docroot/home/index.asp
  • 8. 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 Source: American Cancer Society home page. http://www.cancer.org/docroot/home/index.asp
  • 9. Cancer types ? 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. Have you heard of cancer of RBC?
  • 10. Tumors ? 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. Malignant and Benign tumors Benign tumor Malignant tumor/ cancer cells can grows locally spread by invasion and metastasis Time Paul Graphics
  • 11. 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
  • 12. 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
  • 13. 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. Formation of Cancer Normal cell Normal cell division Apoptosis / programmed cell death Cell damage - no repair Cancer cell division Cell damage - no repair Normal cell No Apoptosis First mutation Second mutation Third mutation Fourth/ subsequent Paul Graphics mutation Uncontrolled growth
  • 14. 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 Mild-dysplasia Cancer (severe Normal Hyperplasia Cancer (invasive) dysplasia) Paul Graphics
  • 15. 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
  • 16. Nature of Cancer 1. Normal tissues are the source of Tumors Tumors are made up of cells Continuity between normal and cancer tissues Undergoes metastasis 2. Tumors arise from many specialized cell types throughout the body 3. Tumors are monoclonal in nature Monoclonality versus Polyclonality 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