iCAMP: Cancer biology tutorial

Anna Konstorum7/10/12

Diagram of colon cancer staging.

Purpose of tutorialsTo 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.

● 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

● Oncogenes

– myc● Transcription factor that regulates transcription of genes that

induce cell proliferation.

– Ras● 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

● 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 organ-specific endothelial cells and angiogenesis.

Model system: colon cancer

2003 Estimated US Cancer Cases

ONS=Other nervous system.*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2003.

Men675,300

Women658,800 210,816 Breast

79,056 Lung/bronchus72,468 Colon & rectum39,528 Uterine corpus26,352 Ovary26,352 Non-Hodgkin

lymphoma19,764 Melanoma of

skin19,764 Thyroid13,176 Pancreas13,176 Urinary bladder62,238 All other sites

Prostate 222,849Lung/bronchus 94,542Colon/rectum 74,283Urinary bladder 40,518Melanoma of 27,012

skinNon-Hodgkin 27,012

lymphoma Kidney 20,259Oral cavity 20,259Leukemia 20,259Pancreas 13,506All other sites 114,801

Men675,300

Women658,800

2003 Estimated US Cancer Deaths*

ONS=Other nervous system.*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2003.

Men285,900

Women270,600

67,650 Lung/bronchus40,590 Breast29,766 Colon & rectum16,236 Pancreas13,530 Ovary10,824 Non-Hodgkin

lymphoma10,824 Leukemia8,118 Uterine corpus5,412 Brain/ONS5,412 Multiple myeloma62,238 All other sites

Lung/bronchus 88,629Prostate 28,590Colon & rectum 28,590Pancreas 14,295Non-Hodgkin 11,436

lymphomaLeukemia 11,436Esophagus 11,436Liver/intrahepatic 8,577

bile ductUrinary bladder 8,577Kidney 8,577All other sites 62,898

How Does Colorectal Cancer Develop?

Janne PA, Mayer RJ. N Engl J Med 2000;342:1960.

Normal colonThe 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):

● 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:● 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/index.html

References

● Colon cancer and colon crypt physiology:

– medschool.umaryland.edu/minimed/powerpoint/greenwaldppt.ppt

– http://www.annualreviews.org/doi/pdf/10.1146/annurev.physiol.67.031103.153530

– Khan Academy, colon cancer histopathology:

● http://www.youtube.com/watch?v=fif5ghe8JM0&feature=relmfu