Scott Cancer Lectures

His notes are on Blackboard. They were good for the first one. Below are my notes for 2 and 3. He stressed studying his notes.
Cancer Notes 2
Terminology and definitions
People mix up words in practice often. It gets confusing. You have to understand a bit of histology. Skin is example.Skin normally has 10-15 layers above basal layer. As skin cells grow they differentiate and eventually slough off. 85% of human cancers derive from epithelial cells. With respect to cancer,this fact is important to understand. Any surface in contact with lumen or outside environment on outside of basement membrane is epithelium. Lungs, GI, salivary glands, liver, pancreas, part of thyroid may be epithelial. Kidney, uterus, included. Tissues that line these surface are epithelial. Cancers of epithelial tissues are called carcinomas. All others are sarcomas (brain, bone, blood vessels, cartilage, blood).
What can happen to an epithelium to lead to cancer?
Hyperplasia- defined in handout. Grows too fast. Does not mean it is cancer. Increased cell proliferation for increased number of cells. Can be normal. Physiological response that is reversible normally. If it goes on long enough tissues can proliferate even without stim. Give rise to cancer. Normal human body takes 10-20 years to get cancer.
Hyperplastic skin is thicker with ridges of basement membrane.
Hypertrophy
More size due to increase size of cells. Bigger cells. Example: lifting weights. Hypertrophy has nothing to do with cancer.
4 key terms to KNOW proliferation, differentiation, apoptosis, senescence.Senescence is process of normal cells losing ability to grow (losing proliferative potential) as you age. Hayflick discovered this concept as a tissue culture phenomenon. Cells divide 30-40 times, stop in G1. Quit growing. Telomerases came out of this. You lose chromosome ends due to loss of telomerase activity. Senescence is not related to differentiation as in neurons. They are terminally differentiated. Not related to telomerases. Senescence did not originally apply to real humans. Progeria and Werner’s syndrome (aging syndromes) led to applying senescence to people.
Metaplasia is primarily a differentiation term. It is an adaptation to stimuli in which one cell type substitutes for another to increase resistance to environmental stress. Lining of bronchs can change from ciliated epithelium to squamous cells due to smoking and/or pollution. Squamous tougher than ciliated. Changes differentiation.
More mixing up of proliferation, differentiation, apoptosis, senescence- more progress towrd cancer.
Dysplasia- screws up proliferation, differentiation, maybe apoptosis and senescence. Alterations in multiple genes, but not malignant. Is progressing towrd cancer. “Carcinoma in situ”= very close to cancer. Almost there. Severe dysplasia- cells dividing all the way to top instead of seeing clear layers differentiated cells.
Invasion is required for cancer. Must become invasive- some cells penetrate basement membrane. Cell crosses membrane and grows where it is not supposed to be-cancer.
A clone of cells in a severe dysplasia can learn to invade.
Tumor- swelling or mass-inflammation, cyst, clot, not necessarily cancer. Could be, or not. Tumor does not equal cancer.
Neoplasia- new growth. Can be quite benign.
Benign tumor- Growth localized.
Metastasis- spread to distant site.
Cancer- malignant, invasive.
Examples of terms for benign tumors- Can have benign or malignant tumors of all tissues. Non-epithelial tissues- oma means benign. Lipoma- benign fat tumor. See his notes for other names.

Epithelial benign growths- papillomas, adenomas, etc. OMA means benign.
Sarcoma is cancer of non-epithelial tissues. Carcinoma means malignant tumor. Adenocarcinoma,
Exception to terminology- melanoma is often term used for malignant pigmented skin cell tumor. Some cancers are named after a famous doctor. Hodgkin’s- malignant tumor of the lymph cells.
Cancer is disease of clonal evolution. Cell clone evolution. What does that mean?See chart at top of page. Field concept of carcinogenesis says that if you expose agroup of cells in a location to cancer causing agents, cells will undergo mutations randomly.
Aneuploidy- abnormal chromosome number. Too many or few. 92 in humans is tetraploidy. Aneuploidy is inappropriate sorting. 95% of cancers are aneuploid. Many premalignant lesions are also aneuploid. Chromosomal imbalance- no mutation required.
Probability is that cells underdosed with chromosomes will die. Overdosed may tend to live. Survival in aneuploidy above 46. Early on, some cells become aneuploid. These events may not happen in the order on chart, so don’t take it as a sequence. But these 5 things happen in course of early cancer. Anything that messes with mitotic spindle (drugs, estrogen, etc) can cause aneuploidy.
Lesion in proliferation gene- mutate oncogene controlling cell cycle and G1 checkpoint does not work. Could screw up any point of cell cycle. Must hit all 5 categories to get cancer.
Mutate differentiation genes- Cell differentiates, malignancy chance slim. Not proliferating if further along in differentiation.
Mess up telomerase- cells no longer senesce. Mess up apoptosis- becomes invasive and malignant.
This is field concept. Clones have different hits in different functions. One may become cancer. Keep zapping, may get mutations in others to make cancer. One clone becomes malignant first. If you sequence each as they become invasive, each clone is different with different mutational profiles. Why is every cancer different? There are lots of genes in the above pathways.
Clonal selection based on field concept- selection for an advantageous trait. Survival advantage. If B is mutated in a way that does not confer advantage, it may die. Each of the categories in the chart fits this theory. Philosophy is idea that “field” is exposed to carcinogens, and clonal evolution and selection goes on. Over years, right hits occur.
Next step is ability to be invasive (selected for ), then metastasis (other set of genes).
Tomorrow- mechanisms of invasion and metastasis.
Cancer stem cell concept suggests that normal stem cells differentiate into cancer. Basal cells with proliferative potential may beome cancer, but skin stem cells sit at certain spots. They are prime targets of carcinogens. Every cancer starts from one cell, but that is a misnomer. The end cells after clonal selection are quite different from the original stem cell. Within the evolving lesion are multiple cells, but one makes it. Cancer is monoclonal disease, but premalignant tumor goes through many selection processes. Variations of this model will probably be correct in the end.
Scott III: Metastasis and Invasion

Multistep Clonal Selection Concept of Carcinogenesis
1. enabling event-genomic instability-aneuploidy
2. preneoplasia:Selection of Cell clones with a proliferation and survival advantage
a.proliferation control autonomy
b. resistance to terminal differentiation
c. resistance to senescence
d. resistance to apoptosis
3. malignant conversion: Development of invasive cancer cell clones
a. disruption of cell-cell interactions
b. production of metalloproteinases and related enzymes that disrupt basement membranes
c. increased cell motility
d. increased angiogenesis
4. Cancer dissemination
a. ability to invade vascular or lymphatic channels
b. potential survival in atypical microenvironments
c. resistance to immune or traumatic activity
d. ability to establish distant cancer foci
e. potential to proliferate and survive at metastatic sites
Advantage of this concept is its explanation of cancer in real world. Takes 20 yrs to go from normal to cancer. Stages along the way happen, and the selection takes time. This theory has a lot of data behind it and makes sense in real people.
Yesterday was premalignant steps. No certain order, but the evidence indicates that aneuploidy occurs early. Human genome is resistant to mutation and had DNA repair mechanisms. If there have to be 140 mutations in 93 genes to make cancer in cell with all those repair mechanisms- probability small unless control is released somehow. Hopkins group looked at first malignant lesion they could study. Smallest polyps called cancer, earliest common characteristic was aneuploidy and genetic instability, plus some of the characteristics in the above list.
1 and 2 above can be characteristics of carcinomas. List above does not apply to leukemias. Leukemias are only 5-7% of cancers.
Dysplastic lesions contain between 4 and 8 different subclones mixed with normal cells. That does not mean there are not more- we have to be able to detect them.
For carconoma to become malignant, must become invasive and metastatic.
What happens during invasion?
Clone loses ability to interact with neighbors- intercellular interaction lost. Cell accentuates interaction with fibronectins and other molecules in basement membrane. Then develops mutations in genes to digest basement membrane, then cell migrates across and starts to invade. This is textbook general process. Problem: What is selective advantage of invading? E-cadherin mutated so cell adhesion is messed up. 20-30 genes have to be mutated for it to get throgh membrane. New discoveries shed light on it. Cells under basement membrane are in stroma. Some of these make factors that tell skin cells to stay up where they belong. The basement membrane is made by eipthelial cells and stromal cells in cooperation, but it is not some kind of lead barrier. IN normal conditions epithelial cells stay where they belong due to signals. This is not all worked out yet.Process becomes more complex. What if a wound creates a hole? Basement membrane is not a magic barrier. Lots of companies are developing drugs and treatments to help wound healing.
Application to cancer-A clone invades, basement membrane looks defective. Actually some of the stromal cells may be mutated and not working right. Cancer may be more than defects in just the cancer cells- may be defects in other cells as well. Clonal selection may not just be for clone, but how clone responds to signal as well. There may be a master switch enabling cells to “hear” signals from other cells- regulation of communication may be key to invasion.
Real lesion- melanoma are embryological descendants of the same ancestors as brain cells. Some call them melanosarcomas. Malignant melanomas are classic invaders. They invade fast. Further it invades, more likely it is to metastasize or spread.
Metastasis
Cancer cells are not all metastatic. All carcinomas are invasive, not metastatic. Not all invasive cells are malignant- immune cells can invade other tissues normally. Lymphocytes, granulocytes, placenta are normally invasive, not cancerous.
All carcinomas are invasive-true.
Cell must be invasive to be malignant, but not necessarily metastatic.
Metastasis means cells can spread to other regions without being in contact with primary tumor. Spreads to distant site, losing contact with primary tumor.
Example of normal metastasis- trophoblasts- some pregnant women placental trophoblasts can be in lung from uterus. Don’t cause cancer, go away after pregnancy. All definitions are not big generalizations. There are exceptions to rules.
Modes metastasis:
1. lymphatic-common
2. Hemotogenous- these 2 are most common. When cancer cells spread hemotogenously- spread most commonly through veins. Arteries have thick muscular walls and veins do not. Mechanically easier to get through vein. Artery will hit capillary bed and tumor could get stuck. No gates like that for veins. Top 2 here most common.
Veins go to lung next. 1st capillary bed is in lung in path from hand. Cells can get stuck in lung. Lymphatic spread- hits lymph nodes. Breast cancer – look at lymph nodes to see spread. Goes to axilla.Any breast cancer in lymph nodes- get chemotherapy.
3. Interstitial complicated
4. gravity through”body spaces” Brain through CNS to spine. Liver to perineum to pelvis.
5. Iatrogenic-induced by doctor. Doctor gets cells on glove when removing cancer and spreads them to other sites.


Cancer can be primary(skin), secondary(lung), tertiary (brain)
Key to metastasis- data shows that if you have tumor size of golf ball, it sheds 1 million cells per day into blood. They mostly die. What happens? Clonal selection. Invasive cells invade vein, cancer cells shed to lung or brain- must survive multistep process to travel, stick, and grow in new environment. Metastatic cells are subclone with different mutation profile.
Primary cancer- grows, becomes vascularized, invades, get in vein in little clumps (intravasate),detach, embolize through veins, arrest at new site, extravasation to invade basement membrane of capillary, grow in new site. One primary tumor can yield a variety of subclones with different metastatic potential.
Take high one. Could reproduce low middle and high after passage through 20 cultures. Genomic instability yields a lot of mutation. Normal cells are genetically stable.
Cancers of different types prefer different places to go. Renal to thyroid or bone. Prostate carcinoma likes arm bone. Breast cancer- lymph nodes, adrenals, bone.
When you treat a cancer, you do clonal selection for cells that are resistant to therapeutic agents. To avoid resistance, people are treated with cocktails these days.