Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and...
Transcript of Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and...
![Page 1: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/1.jpg)
Cancer and OncogenesBioscience in the 21st Century
Linda Lowe-KrentzOctober 29
![Page 2: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/2.jpg)
• Just a Few Numbers
• Becoming Cancer
• Genetic Defects
• Drugs
![Page 3: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/3.jpg)
Our friends and family
0
50
100
150
200
250
to 5
to 15
to 30
to 45
to 60
to 75
to 90
Incidence of cancer
• More mutations as you get older
• More DNA damage due to environment
• One mutation can lead to others
![Page 4: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/4.jpg)
Required characteristics
Original hypothesis – 2 mutations, one in signaling and one in the nucleus.Statistical analysis says more like 5 or 6 mutations probably contribute to cancer.Typically at least one mutation is in a proliferation pathway.Benign cancer requires at least one additional mutation.
![Page 5: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/5.jpg)
Evolution of a cancer cell
![Page 6: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/6.jpg)
Abilities acquiredGrow rapidlyDissociate from neighboring cellsInvade adjacent tissueInvade blood vessels or lymphatic systemEscape immune systemArrest in a new locationGet into target tissueProliferate in new location
![Page 7: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/7.jpg)
Normal Dysplasia
Pre-malignant,
appear abnormal
![Page 8: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/8.jpg)
Carcinoma
Increased cell proliferation
Additional possible changes here include decreased ability to catch mistakes
![Page 9: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/9.jpg)
Malignant
Epithelial to mesenchymal transition.
Cells are able to change characteristics and gain the ability to migrate across barriers or through membranes.
![Page 10: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/10.jpg)
Extravasion
Blood vessels are recruited for nutrient delivery.
![Page 11: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/11.jpg)
One pathwayNormal Epithelium Hyperplastic epitheliumAPC
Me of DNA
Early AdenomaKRasIntermediate AdenomaSmad4
Late Adenoma p53 Carcinoma Invasion and Metastasis
![Page 12: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/12.jpg)
Colon cancer genes (APC)APC > 70%
Binds β-catenin – Colon cell differentiationkRas ~ 50%
Activation of signals for growthDCC > 70%
Cell-cell adhesionp53 > 70%
Lots of changes allowed - carcinomasmad4 ~ 20%
Transcription factor – gene expression
![Page 13: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/13.jpg)
Two ways to change
![Page 14: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/14.jpg)
Growth factors and the cell cycle
Together these pathways result in a complicated plan that results in a balance of proteins and other factors leading to cell growth and division.
![Page 15: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/15.jpg)
SCF is over produced
In many Small Cell Lung Carcinoma patients, lots of SCF (stem cell factor) is produced and the cells also contain the growth factor receptor for this molecule. Therefore, continuous growth signaling occurs.
![Page 16: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/16.jpg)
Ras signaling and cancer
Many mistakes in this pathway have been identified.
![Page 17: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/17.jpg)
Ras (a G protein)Mutant Ras doesn’t remove a Pi easily.
A protein that associates with Ras to help it remove a Pi is defective.
![Page 18: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/18.jpg)
PKD
![Page 19: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/19.jpg)
Types of genes that get mutatedOncogenes – gain of function
Hybrid proteins that change functionOver-production of a proteinActivity increasesYOU ONLY NEED ONE COPY
Suppressor – loss of functionThey can’t check growthUSUALLY YOU LOSE BOTH GENES
![Page 20: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/20.jpg)
Massive changes in the nucleus
Absence of BUB
Missing Check point protein
SKY paintingTranslocations, duplications,
deletions
![Page 21: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/21.jpg)
• Targets – rapidly growing cells.
Early Chemotherapy
![Page 22: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/22.jpg)
Drug Antibodies• Antibodies against growth factor receptors
or modified forms of the receptors.
R
Antibodies might recruit the immune system
Antibodies might block ligand binding to remaining receptors
Antibodies might block receptor function
![Page 23: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/23.jpg)
Small molecule drugs
• Small molecule inhibitors.
• Some of these small molecule drugs are initially effective, but cancer cells can sometimes acquire mutations that make them less effective over time.
![Page 24: Cancer and Oncogenes - Lehigh Universityinbios21/PDF/Fall2008/LoweKrentz_102920… · Cancer and Oncogenes Bioscience in the 21st Century Linda Lowe-Krentz October 29 • Just a Few](https://reader034.fdocuments.us/reader034/viewer/2022042418/5f34aa17e636f0575a38a7a4/html5/thumbnails/24.jpg)
Long term goals
• Ultimately, targeting the stem cells that are cancerous rather than only the most rapidly growing cells will be important.
• Development of specific drugs based on specific cancer situations is also continuing.
• http://www.cancer.gov/