Chapter 5 Neoplasia: A Disorder of Cell Proliferation and Differentiation

Copyright © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

Chapter 5Neoplasia: A Disorder of Cell

Proliferation and Differentiation


Neoplasia• Neoplasms proliferate to form new tissue• They do not wait for signals from the body that the

new tissue is needed• They ignore signals to stop dividing• They often do not mature normally (differentiate)

to do the “job” the tissue is supposed to do• They do not die off (apoptosis) to keep the number

of total cells constant


G2

M

G1 G0

S

R

Mitosis

Inter-phase

Labile cell

Permanent cell

Stable cell

The Cell Cycle

• Normally, the number of cells produced = the number of cells that die

• The total number of cells in the body remains constant


G2

M

G1 G0

S

R

Mitosis

Inter-phase

Labile cell

Permanent cell

Stable cell affected by growth factors

Growth Factors

• Cells divide only when they are told to do so by growth factors

• These cause stable cells to enter the cell cycle and divide


Growth Factors (cont.)

• Attach to receptor proteins

• Which often work by affecting G proteins

• Which turn on enzymes (proteins)

• Which make second messengers

• Which go down inside the cell and make it divide


A Cell Creates Proteins Based on Its Genes


Growth Factor Receptors

• Now this cell is ready to respond to growth factors from another cell

• They bind to the receptors and stimulate cell division


Proto-oncogenes• The normal genes that code for normal proteins

used in cell division– Growth factors– Growth factor receptors– G proteins– Enzymes that produce second messengers– Genes that turn the production of these

proteins on and off


Oncogenes• Oncogenes are mutated proto-oncogenes• They still code for the proteins needed for cell division• But they might produce

– Too much of the protein– An abnormal protein– Protein that turns on all by itself– Protein that is made when it is not needed– Protein that cannot turn cell division off– Protein that should be made by a different cell


Question

Tell whether the following statement is true or false.Oncogenes code for normal proteins used in cell division.


Answer

FalseRationale: The statement describes proto-oncogenes.

Oncogenes are mutated proto-oncogenes that code for abnormal proteins.


This Cell Has Been Infected With a Cancer-causing Virus

• What has changed?

• How could it promote uncontrolled cell division?

• What oncogene is to blame for this?


If You Want to Stop This Cell From Dividing, What Should You Do?• Give a drug that

stops other cells from making the growth factor?

• Give a drug that blocks the growth factor receptors?

• Give a drug that inactivates growth factors in the extracellular fluid?


Here’s Another Cell with the Same Cancer—Would Any of These Treatments Work?

• A drug that stops other cells from making the growth factor?

• A drug that blocks the growth factor receptors?

• A drug that inactivates growth factors in the extracellular fluid?


G2

M

G1 G0

S

R

Mitosis

Inter-phase

Permanent cell

Cyclin proteins measure whether the cell has grown large enough to divide

Cyclins check that the DNA has been correctly duplicated

Cyclins make sure the cell has made the proteins needed to separate the chromosomes

Checkpoints in Cell Division


Tumor Suppressor Proteins• The checkpoints usually stop the division of mutated cells• They keep most mutations from developing into cancer• The proteins that control the checkpoints are called

tumor suppressor proteins– Cyclins– Cyclin-dependent kinases– Cyclin inhibitors (p53)

• If the genes for these proteins were mutated, you might get many more cancers


Cell Division Requires Duplicating the DNA

• Telomeres: DNA sequences at the ends of the chromosomes – The enzymes that duplicate DNA attach here– The end of the telomere does not get duplicated– What will happen to the telomere as the cell

continues dividing?• A man has a mutation that causes some of his cells

to rebuild their telomeres after every division. Is this a good thing or a bad thing? Why?


• Initiation: initial mutation occurs

• Promotion: mutated cells are stimulated to divide

• Progression: tumor cells compete with one another and develop more mutations, which makes them more aggressive

Oncogenesis


G2

M

G1 G0

S

R

Mitosis

Inter-phase

Labile cell

Permanent cell

Stable cell

Normal Cells • Normally, after

a cell has divided, it becomes either a permanent cell or a stable cell

• These cells stop reproducing and continue working for the body


Differentiation • “Grown-up” cells are called differentiated because they look different from one another

• You can tell a spleen cell from a skin cell


Cell Mutation• When differentiated,

“working” cells mutate, they form differentiated “working” tumors— benign tumors

• When undifferentiated, rapidly dividing cells mutate, they form rapidly dividing tumors—malignant tumors


Question

When a well-differentiated cell mutates, is it more or less likely to become a malignant tumor?

a. Moreb. Lessc. Degree of differentiation has no bearing on whether a

tumor is malignant or benign.


Answer

b. LessThe more differentiated a cell is when it mutates, the more

likely it is to become a benign tumor. If poorly differentiated cells mutate, the tumor is more likely to become malignant.


Naming Tumors• Benign tumors: tissue name + “-oma”• Malignant tumors (cancers)

– Epithelial tissue: tissue name + “carcinoma”– Mesenchymal tissue: tissue name + “sarcoma”


Benign Tumors• Contain cells that look like normal tissue cells• May perform the normal function of the tissue (like

secreting hormones)– This may lead to oversecretion

• Usually have a capsule around them• Usually do not invade neighboring tissues• But they can damage nearby organs by compressing

them


Benign Uterine Tumor With Clearly Defined Edges


Malignant Tumors• Contain cells that do not look like normal adult cells• These cells divide rapidly, so:

– Tumors grow quickly– Cells mutate faster and can change type

• The tumor does not have clear boundaries and sends “legs” out into surrounding tissue (the word cancer means “crab” and is based on these crablike legs)

• Do not perform the normal functions of the organ– May secrete hormones associated with other

tissues• Can compress and/or destroy the surrounding tissues


Malignant Lung Tumor Invades Surrounding Tissues


Question

What gross anatomic feature of the lung tumor you just saw makes it likely to be malignant?

a. The tumor is growing quickly.b. The tumor has a poorly defined border.c. Cells do not look like normal cells.d. All of the abovee. b and c


Answer

e. b and cRationale: Gross anatomy can be viewed with the naked

eye. Although rapid growth is a characteristic feature of malignant tumors, this cannot be determined from the slide. However, the lack of a clear border and the different appearance of the group of cancer cells can be clearly seen.


Metastasis• Cells in a primary

tumor develop the ability to escape and travel in the blood

• Imagine you were a cancer cell. What abilities would you need to survive in the tumor?

• What abilities would you need to metastasize?


Scenario• Mrs. T has liver cancer• Her doctor did an initial molecular diagnosis and

put her on targeted therapy; the tumor shrank by almost 75%

• Two years later the tumor was growing again, and this time it did not respond to the drug

• Last year she was diagnosed with metastases in her femur that have not responded to the drug either

• Mrs. T wants to know why the cancer cells stopped responding. Are they not all the same cells?


Manifestations of Cancer• Changes in organ function (organ damage,

inflammation, and failure)• Local effects of tumors (e.g., compression of

nerves or veins, gastrointestinal obstruction)• Ectopic hormones secreted by tumor cells

(paraneoplastic disorders)• Nonspecific signs of tissue breakdown (e.g.,

protein wasting, bone breakdown)


Changes in Organ Function• Organ failure• Benign tumors may cause overproduction of

normal organ secretions• Malignant tumors may occasionally cause

overproduction (as in thyroid cancer), but more commonly decrease production of normal organ secretions


Question

Why do malignant tumors usually cause a reduction in the amount of hormones the affected organ produces?

a. Organ damageb. Inflammation of the organc. Organ failured. All of the abovee. a and c


Answer

d. All of the aboveRationale: Effects of malignant tumors on the organ

system include inflammation and damage, which ultimately lead to organ failure. In all cases the organ cannot function optimally, and is unable to secrete the normal/typical amount of hormones.


Local Effects of Tumor Growth• Bleeding• Compression of blood vessels

– Superior vena cava syndrome– Portal hypertension

• Compression of lymph vessels – Edema, ascites, effusion

• Compression of hollow organs• Compression of nerves

– Pain, paralysis


Paraneoplastic Syndromes• Cancer cells produce hormones or hormone-like

proteins– ADH– ACTH– PTH-related protein

• Cancer cells produce proteins that affect clotting• Paraneoplastic neurologic disorders


Generalized Effects of Cancer• Cancer cachexia syndrome

– Weight loss– Muscle wasting– Weakness– Anorexia– Anemia

Chapter 5 Neoplasia: A Disorder of Cell Proliferation and Differentiation

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