iCAMP: Cancer biology tutorial
Diagram of colon cancer staging.
Anna Konstorum
7/10/12
Purpose of tutorials
To provide a focused background on the biology of tumors and
cancer cells in order for students to better understand the questions
that cancer biologists are currently trying to answer.
We will concentrate on the model system relevant to the experimental
data, which is the colon and colon carcinoma.
The second tutorial will cover basic experimental methods that
biologists use to answer the questions that arise in their research,
again with particular attention to the experiments that created the
images used for iCAMP.
What is cancer?
Normal cells are subject
to signals that dictate
whether the cell should
divide, differentiate into
another cell, or die.
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Cancer can be defined as a
disease in which a group of
abnormal cells grow
uncontrollably by disregarding
the normal rules of cell division.
What is cancer?
●
●
Cancer cells develop a degree of autonomy from
these signals, resulting in uncontrolled growth and
proliferation.
Almost 90% of cancer-related deaths are due to
tumor spreading == metastasis.
Cancer is clonal in origin
Cancer is clonal in origin
Six hallmarks of cancer
Immortality
●
Cells taken from the excised
tumor of Henrietta Lacks, over
sixty years ago, are still used in
research all over the world.
(Story of her life a bestseller on
Amazon!)
Sustained growth signals (== oncogene activation)
Bypass anti-growth signals (== tumor suppressor
gene deactivation)
Well-known oncogenes and tumor
suppressors
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Oncogenes
–
myc
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–
Ras
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Transcription factor that regulates transcription of genes that
induce cell proliferation.
GTPase: hydrolyses GTP into GDP+P on proteins that regulate
cell proliferation; activated by growth factors, but can mutate
to be constitutively active.
Tumor Suppressors
–
p53
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–
Activates DNA repair proteins in response to DNA
damage; can induce growth arrest or apoptosis.
pRB
●
Inhibits cell cycle progression until a cell is ready to
divide.
Avoidance of cell death (apoptosis)
Ensuring blood vessel growth (angiogenesis)
1. Angiogenic factors secreted by tumor cells activate vascular
endothelium lining blood vessels.
2,3, 4: Proteases degrade the basement membrane of endothelial cells,
causing them to be less adherent (hence more motile), and vascular
permeability is increased.
5, 6: Endothelial cells
migrate to angiogenic
stimulus and enter the
cell cycle.
7-8: New vessels mature
and become established
in the tumor.
Metastasis
The outcome of the
metastatic process
depends on continuous
interactions between
unique metastatic
cells and a specific
organ
microenvironment
that includes organspecific endothelial
cells and angiogenesis.
Model system: colon cancer
2003 Estimated US Cancer Cases
Prostate
222,849
Lung/bronchus 94,542
Colon/rectum 74,283
Urinary bladder 40,518
Melanoma of
27,012
skin
Non-Hodgkin
27,012
lymphoma
Kidney
20,259
Oral cavity
20,259
Leukemia
20,259
Pancreas
13,506
All other sites 114,801
Men
Men
675,300
675,300
Women
658,800
ONS=Other nervous system.
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2003.
210,816
79,056
72,468
39,528
26,352
26,352
19,764
19,764
13,176
13,176
62,238
Breast
Lung/bronchus
Colon & rectum
Uterine corpus
Ovary
Non-Hodgkin
lymphoma
Melanoma of
skin
Thyroid
Pancreas
Urinary bladder
All other sites
2003 Estimated US Cancer Deaths*
Lung/bronchus 88,629
Prostate
28,590
Colon & rectum 28,590
Pancreas
14,295
Non-Hodgkin
11,436
lymphoma
Leukemia
11,436
Esophagus
11,436
Liver/intrahepatic 8,577
bile duct
Urinary bladder 8,577
Kidney
8,577
All other sites
62,898
Men
285,900
Women
270,600
67,650
40,590
29,766
16,236
13,530
10,824
Lung/bronchus
Breast
Colon & rectum
Pancreas
Ovary
Non-Hodgkin
lymphoma
10,824 Leukemia
8,118
Uterine corpus
5,412 Brain/ONS
5,412 Multiple myeloma
62,238 All other sites
ONS=Other nervous system.
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2003.
How Does Colorectal Cancer Develop?
Janne PA, Mayer RJ. N Engl J Med 2000;342:1960.
Normal colon
The colon is the last part of the digestive system, and extracts water and salt from
solid wastes before they are eliminated from the body.
Colon crypts, found in the epithelial lining of the colon, secrete various enzymes
and mucus to help with nutrient and water absorption.
Since cells in crypt are continuously worn away, they are constantly being
renewed, hence placing the region at larger risk for development of cancer.
Normal colon
Colonoscopy
provides
samples for
histological
analysis.
This is a sample
of normal colon
tissue.
Source:
http://www.youtube.com/watch
?
v=C0frzmxc5KU&feature=relm
fuM0
Colon hyperplasia
Colonoscopy
provides samples
for histological
analysis.
This is a sample of
inflamed colon
tissue (hyperplasia),
not considered
cancerous.
Source:
Khan Academy tutorial on
Colon cancer:
http://www.youtube.com/watch
?v=fif5ghe8JM0
Adenoma
Colonoscopy
provides samples
for histological
analysis.
This is a colon
polyp, classified as
'pre-cancerous'
lesion.
Source:
http://www.youtube.com/watch?
v=CGrbnripinU&feature=relmfu
Carcinoma
Colonoscopy
provides samples
for histological
analysis.
This is a colon
carcinoma, note the
that the cancer has
grown through the
muscle.
Source:
http://www.youtube.com/watch?
v=KyJs9H0vzTM&feature=relmfu
Staging of Colorectal Cancer
In the second tutorial, we try to answer
(or at least introduce the questions):
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What are cancer stem cells, and how are they
'organized' in tumors?
How do microenvironmental interactions
impact tumor development?
What are some methods that biologists use to
better understand cancer in the laboratory?
What are the methods that were used to
produce the experimental results that we are
currently analyzing?
References
●
General Cancer Biology:
–
Introduction to Cancer Biology, Dr. Momna Hejmadi:
●
–
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http://grammars.grlmc.com/wsmbio2012/Download/Slides
/Xu/introduction-to-cancer-biology.pdf
Cancer Medicine, 5th Edition:
http://www.ncbi.nlm.nih.gov/books/NBK20777/
Cancer vasculogenesis:
–
http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/lymboussaki/in
dex.html
References
●
Colon cancer and colon crypt physiology:
–
medschool.umaryland.edu/minimed/powerpoint/greenwaldp
pt.ppt
–
http://www.annualreviews.org/doi/pdf/10.1146/annurev.physi
ol.67.031103.153530
–
Khan Academy, colon cancer histopathology:
●
http://www.youtube.com/watch?
v=fif5ghe8JM0&feature=relmfu