BIOL 445 Cancer Biology

Mark Peifer and Bob Duronio

Spring 2015

BIOL 445

In Bio 445 we combine the approaches of Bio 202 + Bio 205with the current scientific literatureto study the family of diseases known as cancer

You may not believe it but by the end of the semesterThis will make sense!

Hanahan and Weinberg, Cell 100:57-70 (2000)

Virtually everything you’ll need is found at:

http://www.bio.unc.edu/Courses/2015Spring/Biol445/

It’s a REALLY good idea to look through this carefully THIS WEEK

AND

Check back frequently for updates or changes

We will also us the course Sakai site for online quizzes, Blogs, and as a place for a discussion forum

BIOL 445Textbooks-The Biology of Cancer by Robert Weinberg 2nd Edition

Grading- Exams (20% X 2 midterms + 25% final) = 75- Presentations = 15- Classroom discussion, online and in-class evaluations = 10

What are you responsible for?- Lectures (attendance AND participation)- Papers and assigned textbook reading(on website)-Your project- literature search and presentation

Your Project

- Choose a topic

- Read the posted review paper

- Do a thorough literature research, including primary data on the gene and the disease

- Make a poster and present it to your peers

- The final exam will cover ALL posters

Cancer: a family of diseases

caused by our own cells gone wrong

Cancer is number 2

and rising relative to heart disease!

CDC

ONS=Other nervous system.Source: American Cancer Society, 2009.

But as we’ll see, Cancer is not one disease, its many

Lifetime Probability of Developing Cancer, By Site, Men, US, 2007-2009

SiteRisk

All sites 1 in 2

Prostate 1 in 6

Lung and bronchus 1 in 13

Colon and rectum 1 in 19

Urinary bladder 1 in 26

Non-Hodgkin lymphoma 1 in 43

Melanoma 1 in 40

Kidney 1 in 49

Leukemia 1 in 63

Oral Cavity 1 in 67

Stomach 1 in 92

Source: ACS http://www.cancer.org/Cancer/CancerBasics/lifetime-probability-of-developing-or-dying-from-cancer

Lifetime Probability of Developing Cancer, By Site, Women, US, 2007-2009

Site Risk

Source: ACS http://www.cancer.org/Cancer/CancerBasics/lifetime-probability-of-developing-or-dying-from-cancer

All sites 1 in 3

Breast 1 in 8

Lung & bronchus 1 in 16

Colon & rectum 1 in 21

Uterine corpus 1 in 38

Non-Hodgkin lymphoma 1 in 52

Melanoma 1 in 63

Pancreas 1 in 69

Ovary 1 in 72

Kidney 1 in 83

Urinary bladder 1 in 87

We are making progress, however!!

March 28.2012

Cancer is NOT an infectious disease

Cancer is NOT an infectious diseaseInstead it illustrates the challenge of understanding how genetics and the

environment combine to cause disease

To understand what goes WRONG,we need to understand

how things normally go right

Cells within a tissue are normally highly organized and tightly regulated

e.g. intestine e.g. skin

Cancer: an aberration of normal development

Cancer cells exhibit behaviors found in normal cells during development,

differentiation, and homeostasis

Cancer: an aberration of normal development

Cancer cells exhibit behaviors found in normal cells during development,

differentiation, and homeostasis

However, cancer cells put together suitesOf cell behaviors in problematic ways

And do so out of normal regulatory controls

All cancers have a genetic basis--they are diseases of our own cells gone wrong

Sometimes inherited mutations play a role.e.g., Familial adenomatous polyposis (FAP) =inherited predisposition to colon cancer

However, most cases result from the Slow accumulation of

Somatic mutations

Cancer results from a

series of mutations, each further

altering the cell

Lodish et al.Fig. 24-6

The last two years has seen a revolution in our knowledge of the full array of mutations in many tumor types

Most normal cells have a limited potential to divide

senescent cells

Properties of Cancer Cells

Normal stem cells can divide indefinitely, but under tight control

Self-renewing stem cell

Differentiated cells

Cancer cells are "immortalized”,just like stem cells, but w/o control

Properties of Cancer Cells

Self-renewing stem cell

Differentiated cells

Cancer cell

Most Normal cells differentiate

But stem cells do NOT

differentiate

Like normal stem cells Cancer cells do not differentiate

tumor

Figure 20-29 Molecular Biology of the Cell (© Garland Science 2008)

Most normal cells stop proliferating under contact inhibition

in vitroin vivo

Figure 20-29 Molecular Biology of the Cell (© Garland Science 2008)

Cancer cells are not under contact inhibition

However cells of early embryosalso lack contact inhibition, but then gain it at themid-blastula transition

Normal

“Transformed”

Cancer cells have alterations incell adhesion

and the cytoskeleton

Look out-Here I Come!

Cell from:www.basic.northwestern.edu/ g-buehler/micropl.jpg

These changes in cell shape and behaviorare shared by many migrating cells,including those that migrate into wound sites

Late stage cancer cells are invasive

Figure 20-17 Molecular Biology of the Cell (© Garland Science 2008)

normal tissue

invasive tumor

Normal cells can be invasive at the right time and place

Seward Hung

Normal cells that are starved for O2 Induce Angiogenesis

Consequences 1. Nutrients and oxygen are supplied to the tissue

Can’t breath!Send Blood vessels

Cancer Cells also Induce Angiogenesis

Consequences 1. Nutrients and oxygen are supplied to the tumor2. New blood vessels provide as easy way out

Some properties of Cancer Cellsinvolve evading normal behaviors that

limit growth and prevent damage

Normal cells may undergo apoptosis

as part of a developmental program

when cells become “dangerous” (e.g. DNA

damage)

Properties of Cancer Cells

Cancer cells escape apoptosis

blue cells = breast cancer cells

yellow cells = apoptotic cells

Dave McCarthy and Annie Cavanagh

Cancer: an aberration of normal development

Cancer cells exhibit behaviors found in normal cells during development,

differentiation, and homeostasis

However, cancer cells put together suitesOf cell behaviors in problematic ways

And do so out of normal regulatory controls

- Cancer cells do not form differentiated tissues

- Cancer cells are not under contact inhibition

- Cancer cells are "immortalized”

- Cancer cells are invasive

Properties of Cancer Cells

- Cancer cells escape apoptosis

This Lecture- Properties of cancer cells

- Tumor progression

- What causes cancer?

- Accumulation of mutations

Figure 20-9 Molecular Biology of the Cell (© Garland Science 2008)

Cancer develops through gradual changesin cell morphology and properties

Tumor Progression

Tumor = abnormal growth of solid tissue

benign- self contained

malignant- invasive

Figure 20-17 Molecular Biology of the Cell (© Garland Science 2008)

Metastasis is a difficult and dangerous process both for the tumor cell and the host!

This is what you do NOT want

Cellular changes required for metastasis

Figure 20-44 Molecular Biology of the Cell (© Garland Science 2008)

This Lecture- Properties of cancer cells

- Tumor progression

- What causes cancer?

- Accumulation of mutations

What Causes Cancer?

- Random mutations (mistakes at the assembly line or induced by environment)

- Inherited mutations (pre-disposition)- Viral infections (cervical cancer and a few rare

types)

Cancer : Accumulation of Mutations

The first association between occupation and cancer

Percivall Pott found that chimney sweeps show substantially higher rates of skin cancer

British chimney sweeps didn’t do anything about it

Danish chimney sweeps : a daily bath after work

Result: significantly lower rates of skin cancer amongst Danish versus British chimney sweeps,

even a century later

A happy Danish chimney sweep

at work

with the family

Figure 2.21b The Biology of Cancer (© Garland Science 2007)

Yamagiwa

Yamagiwa took it one step further

Coal tar condensates induced skin carcinoma in rabbits

Chemicals can directly induce cancer

Cancer can be studied in the lab

Figure 20-20b Molecular Biology of the Cell (© Garland Science 2008)

Carcinogens = agents that contribute to the formation of a tumor

Can YOU see the trend in the data?

This Lecture- Properties of cancer cells

- Tumor progression

- What causes cancer?

- Accumulation of mutations

Cancer often starts with a single mutation

HoweverOne mutation is not enough !!

Heard of natural selection?

Figure 20-7 Molecular Biology of the Cell (© Garland Science 2008)

The fact that cancer is a multi-step process is reflected in correlation between age and incidence of cancers

Cancer cells also accumulate chromosomal abnormalities,especially late in the process

Figure 20-13 Molecular Biology of the Cell (© Garland Science 2008)