Chapter 16- Cancer

Where we’re going

• Characteristics of cancer cells

• Some names

• Convince you that cancer is a result of multiple genetic defects

• Molecular genetics of cancer

• We’ll be connecting cancer to growth and signaling.

• A few treatments

Why this is important

• About 1 in 4 of us get cancer, 1 in 5 die of it- at least.

• It’s very much a disease that can be understood at the molecular level.

• Our understanding has not resulted in the cures we’d like

No particular relevance- painted by Van Gogh in the 1880’s!

Cancers vary in terms of getting a type of cancer and dying from that type

Data 2000-2003

Basic Properties of cancer cells

• Uncontrolled- grow at the usual rate, but then keep growing when other cells would normally stop- ignore stopping signals, or grow w/o added signals.

• Invasive

• Immortal- normal cells undergo senescence- telomerase is 1 factor.

• Chromosomal abnormalities- aneuploid

Well-behaved- stop growing when they cover the dish.

Not well-behaved- keep growing after they cover the dish.

Internal signals allow serum-free growth

• Names: • A. tumor/neoplasm: clone of cells

capable of uncontrolled growth;• benign: contained• malignant: spreading • B. classified by tissue of origin:• carcinoma-epithelial tissue• sarcoma- mesodermal origin: muscles,

connective tissue, vascular tissue• leukemia/lymphoma- blood forming

(hemopoietic) cells

Origins of cancer cells

• Clonal, but highly mutable

• Chronic myelogenous leukemia-translocation from 22 to 9 (Philadelphia chromosome)

More than one defect:

• 1016 cell divisions in a lifetime;

• even at a mutation rate of 1/106, we'd have 1010 mutations in every gene! Thus, it may take 3--7 events, in the same cell, to make it cancerous. evidence:

• 1. frequency of cancer, peryear, goes up with age- accumulated mutations. Molecular evidence agrees with this.

• http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.4270 Colon cancer of women

in England & Wales

• 2. tumor progression: e.g., cervical carcinoma: the cells can be in a precancerous stage; undifferentiated; some may be immortal; yet not be cancerous. Only a fraction of the precancerous cells become cancerous. Thus, the changes are typically sequential, rather than having to be simultaneous. Very much an evolutionary event!

Normal- small nuclei

Precancerous- carcinoma in situ

• 3. Initiator/promoter studies: Fig. 23-19, MBOC:

• http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.4300

• Many cells revert to a less differentiated stage- carcinoembryonic antigen is expressed in embryos, and also in cancers.

The initiator is mutagenic, while the promoter stimulates growth- the mutant population increases, increasing the likelihood of further mutations

4. Molecular evidence: With the advent of cloned oncogenes,it's been possible to add such genes to normal cells or animals, anddetermine the results. a. 3T3 cells- already abnormal; single added oncogene makes them cancerous. b. normal cells require two oncogenes: myc & ras both result intransformation. Same results with transgenic mice. 23-30http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.4325

These are mice with transgenic, overexpressed oncogenes.

A typical progression of cancer

So what causes all those mutations?

• Life

• Maybe mutagens

• Viruses in some cases

• Diet can have an effect

However, correlation doesn’t necessarily mean causation…

How are cancer cells different in gene expression?

• We can use microarrays to find out!

• 1000’s of gene-specific sequences.

• Isolate mRNA from cell, turn into cDNA

• Hybridize to sequences

• Can quantify amounts.

ALL- lymphoid- lymphocytes

AML: myeloid- granulocytes, macrophages, dendritic cells

Sometimes this helps- or not

IV. Molecular genetics of cancer: Two basic effects that genes can have on cell

growth;

• A. stimulate growth: oncogenes; genes that are normally turned on as part of growth, now unusually active. Dominant mutations; also DNA tumor virus genes.

• B. inhibit excessive growth: some genes seem to be there to keep oncogenes in line; these mutations tend to be recessive. Tumor suppressor genes,

• Cell fusion studies can differentiate between these- Suppressors are recessive to normal, and oncogenes are often dominant over normal.

• C. types of stimulatory genes:• 1. DNA tumor virus genes:

non-permissive infections result in excessive growth: human viruses infecting hamsters. The virus produces a protein that, in one case binds and inactivates two of the major tumor suppressor genes- Rb and p53, thus allowing uncontrolled DNA replication. (Fig 23-35)

• http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.4334

2.Oncogenes: most were discovered in RNA tumor viruses: carried by certain tumor viruses. We have homologous genes- proto-oncogenes.

Types- Cell signaling (RAS), cell regulating, growth factors, GF receptors, transcription factors, anti-apoptosis proteins.

With more changes…

Ways to become a bad oncogene

New copy, overexpressed, comes in from retrovirus! Retrovirus activates, by insertion, nearby proto-oncogene!

These are all oncogenes

Tumor suppressor genes

• Tend to halt unregulated cell growth-cell cycle control w/ damage, or inappropriate signals.

• Need TWO bad copies before problems occur- recessive.

With further mutations

Retinoblastoma gene- hereditary cancer w/ 90% penetration- born w/ 1 bad copy. It normally is stopping S phase. E2F is major TF, turns on many genes.

P53- the guardian of the genome!!

• Transcription factor

• Made but unstable

• DNA damage (ATM-> CHK2->phosphorylated/stable)

• P21 transcribed- binds CDK/Cyclin, stops G1-S transition.

• Activates apoptotic genes as well

So, effects are indirect, rather than direct.

Not apoptosis, necessarily

??? Which cancers do you think this is associated with?ATM, Chk2,

When p53 is deleted, cancers are less susceptible to death..

Cancer Therapy

• The problem: they are us! Kill them, kill us!• Typical chemotherapy or radiation takes

advantage of fairly subtle differences between them and us in order to kill them- makes us SICK! Plus, many are carcinogenic-radiation

• Some newer treatments- immunotherapy, passive and active.

• “Silver bullet” approaches

Passive Immunotherapy

• Antibodies against a protein that is unique or overexpressed on cancer cells can kill the cells.– Herceptin- Ab that’s competitive inhibitor to

growth factor- binds to the receptor, doesn’t stimulate it, may cause endocytosis.

– Rituxan- Ab against B cell surface protein; kills certain non-Hodgkin’s lymphoma cells.

Active Immunotherapy

• Coley’s story…Cytokines produced during a bacterial infection include Tumor necrosis factor!

• Cancer cells-> cultivate-> use to find immune cells that react against them-> cultivate-> reintroduce into patient.

• Sometimes works…

Targeting Oncogene activity: Gleevec

• Inhibits the receptor protein kinase activity of Abl- one of the receptor oncogenes-

• The one fused to immunoglobulin in the Philadelphia chromosome- Chronic myelogenous Leukemia.

• Revolutionized treatment of this disease.

Things to know

• Characteristics of cancer cells, types of cancers

• Why we’re convinced that it’s a multi-step process

• DNA tumor virus genes, oncogenes, tumor suppressors.

• Ways proto-oncogenes go bad

• Cancer therapy