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Abnormal Cell Growth 1

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					 Abnormal Cell Growth.1




Su Dharmawardhane Flanagan, Ph.D.
     surangi@mail.uccaribe.edu
 http://www.sbs.utexas.edu/dharma/
       Cell Biology and Biochemistry Course
                       2007
    • Introduction
    • Cell biology of neoplastic transformation
       – Multiple mutation model
       – Cancer stem cells
    • Tumor initiators and promoters
    • Molecular Genetics of Neoplastic Transformation
        – Oncogenes, proto-oncogenes
        – Tumor suppressors
        – Molecular basis of the major inherited cancer syndromes
    • Strategies for cancer therapy


Chap. 24, Molecular Biology of the Cell, Alberts et al.,4th Edition, Garland
Science, 2002.
The Hallmarks of Cancer, Hanahan and Weinberg. Cell, 2000, 100:57-70.
                                US Mortality, 2002
                                                                           No. of           % of all
             Rank      Cause of Death                                      deaths           deaths




        1.     Heart Diseases                                                696,947 28.5

        2.     Cancer                                                        557,271 22.8

        3.     Cerebrovascular diseases                                      162,672         6.7

        4.     Chronic lower respiratory diseases                            124,816          5.1

        5.     Accidents (Unintentional injuries)                            106,742         4.4




Source: US Mortality Public Use Data Tape 2002, National Center for Health Statistics, Centers for Disease Control
and Prevention, 2004.
                           Change in the US Death Rates* by Cause,
                                         1950 & 2002
                  Rate Per 100,000
        600        586.8

                                                                                                 1950
        500
                                                                                                 2002
        400


        300
                             240.1
        200                                                                                     193.9    193.4
                                             180.7


        100
                                                        56.0           48.1
                                                                                  22.5
           0

                          Heart               Cerebrovascular              Pneumonia/                   Cancer
                        Diseases                 Diseases                   Influenza

* Age-adjusted to 2000 US standard population.
Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.
2002 Mortality Data: US Mortality Public Use Data Tape, 2002, NCHS, Centers for Disease Control and
Prevention, 2004
           2005 Estimated US Cancer Deaths*
Lung and                                   Men      Women     •27% Lung and
bronchus               31%                295,280   275,000   bronchus
Prostate               10%                                    •15% Breast
Colon and rectum 10%                                          •10% Colon and rectum
Pancreas                 5%                                   • 6% Ovary
Leukemia                 4%                                   • 6% Pancreas
Esophagus                4%
                                                              • 4% Leukemia
Liver and intrahepatic3%
   bile duct                                                  • 3% Non-Hodgkin
                                                                     lymphoma
Non-Hodgkin                   3%
  Lymphoma                                                    • 3% Uterine corpus
Urinary bladder          3%                                   • 2% Multiple myeloma
Kidney                   3%                                   • 2% Brain/ONS
All other sites               24%
 ONS=Other nervous system.
                                                              •22%   All other sites
 Source: American Cancer Society, 2005.
Carcinomas: Cancers
arising from epithelial
cells

Leukemias: From
hemapoietic (blood
progenitor) cells

Sarcomas: From
connective tissue or
muscle cells
(mesenchymal)

Lymphomas: From
lymphatic cells

Gliomas: From brain or
spinal cord
      Cell Biology of Neoplastic
            Transformation
• Neoplastic Transformation: Proliferate in
  defiance of normal growth controls
New and abnormal growth of tissue, which may
  be benign or cancerous
• Cancer cells grow and divide uncontrollably
• Cancer is the result of breakdown of signaling
  mechanisms that regulate normal cell
  proliferation, differentiation,
  survival/apoptosis, and migration/invasion
• Mechanisms that are dysregulated in cancer
  need to be understood for rational cancer
  therapy
Cancer Cells   1. Divide in defiance of the
               normal constraints: benign
               tumor (neoplasm)
               Adenoma: benign epithelial
               tumor with glandular
               organization

               2. Invade surrounding
               tissue and colonize
               territories normally
               reserved for other cells:
               malignant tumor =
               Adenocarcinoma

               3. Invade and colonize
               territories normally
               reserved for other cells:
               metastatic tumor
      Most cancers derive from a single
               abnormal cell
                                                 X-inactivation
                                                 mosaic from a
                                                 cancer that was
                                                 probed for a X-
                                                 linked marker
                                                 gene.




Aberration in cancer cell has to be heritable:
• Genetic Change
• Epigenetic Change (no change in DNA sequence)
         Multiple Mutation Model




Tumors grow clonally from cells that have acquired multiple mutations.
Tumors can be heterogenous.
                                                               pp. 105-111




Stem cells have the ability to perpetuate themselves through self-renewal
and to generate mature cells of a particular tissue through differentiation.
Cancer stem cells are more potent at self renewal and have lost the ability
for population control.
Cancer stem cells are resistant to therapy




Cancer stem cells are a phenotypically distinct subset of cells in a tumor
that have the capacity to significantly proliferate and form new tumors.
Cancer stem cells have the same cell surface markers as normal
haematopoietic stem cells.
Cancer stem cells can go through periods of dormancy and are
responsible for tumor recurrence.
Carcinogenesis: cancer
initiation can be linked
to mutagenesis, due to
alteration of a growth
regulatory gene
Clonal tumor
population: arises from
a cell that can divide
faster
Progression: A tumor
develops through
repeated rounds of
mutation and
proliferation to give rise
to a dominant clone of
malignant cancer
1) Hyperplasia – an increase in size
   of an organ or tissue due to
   increase in the number of cells
2) Dysplasia – an abnormal cellular
   proliferation in which there is a
   loss of normal architecture and
   orientation (precursor)
3) Carcinoma in situ – malignant
   neoplasm of epithelial origin that
   has NOT penetrated through the
   basal lamina
4) Invasive Carcinoma – tumor cells
   have penetrated the basal lamina
   into the connective tissue
   underneath but not spread via the
   circulation yet
5) Metastatic Carcinoma – tumor
   cells have spread throughout the
   body and established new tumors
   at other sites
      Growth of a typical tumor: Breast




http://www.breastcancer.org/type_breast_cancer_picture.html
             Cancer Progression




Intraductal carcinoma Infiltrating ductal carcinoma Invasive lobular carcinoma




 Normal     Pre-cancerous    Invasive cervical cancer
             dysplasia
Characteristics the
pathologist looks for
when diagnosing a
tumor as malignant
Cancer cells escape limits on proliferation
                              • Cancer cells have
                              damaged DNA
                              • The damage is not
                              repaired
                              • Cells with impaired DNA
                              divides uncontrollably
                              • Increased telomerase
                              activity
                              • Anchorage independent
 Transformed   Normal
                              growth
                              •Lack contact inhibition
                              • Ignore replicative
                              senescence or terminal
                              differentiation
                Cancer Metastasis

Proliferation



Intravasation


Dissemination


   Survival



Extravasation


Proliferation

 Many signaling pathways can be dysregulated during
 cancer metastasis
Cancer Development
         Tumor Initiators:
         • Mutagenic
         • Cause genetic changes
         e.g. DMBA
           (dimethylbenzanthracene),
           UV, radiation
         Tumor Promoters:
         • Not mutagenic
         • Stimulates cell
           proliferation
         • Exposure over period can
           cause cancer in tissue
           damaged by an initiator,
         e.g. Phorbol esters
Ames Test for Mutagenecity
              Chemical Mutagens




Tumor Initiators: Cause permanent genetic changes that can
remain dormant for years
                      Tumor viruses
DNA viruses
1. Hepatitis B: Liver cancer
2. SV40 and Polyoma: no human tumors
3. Papilloma: Cervical and anogenital carcinomas
4. Adenovirus: None
5. Herpes: Burkitt’s lymphoma, nasopharyngeal carcinoma,
   Kaposi’s sarcoma

RNA viruses
1. Retroviruses: Adult T cell leukemia
2. Hepatitis C: Liver cancer
Viruses can cause cancer by integration of viral genes into
host chromosomes
Papilloma virus in uterine cortex
Rous sarcoma virus: contains first viral oncogene Src
 Uncontrolled regulatory mechanisms in cancer
                 progression
1. Increased proliferation
2. Increased survival
3. Suppressed differentiation
4. Immortalization
5. Decreased apoptosis
6. Loss of adhesive properties
7. Angiogenesis
8. Increased invasive properties
9. Genetic instability: aneuploidy (variation in
chromosome number), cannot repair DNA damage
Cell, 2000, 100:57-70. The Hallmarks of Cancer Hanahan and Weinberg

				
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