Wk5 Cancer Biology - Baum

Question 1

Baum Wk5

hyperplasia

Answer 1

increased cell proliferation. Reversible

Question 2

Baum Wk5

dysplasia

Answer 2

loss of uniform appearance and architectural disruptions (really bad looking cells are called anaplastic). Dysplasia is often indicative of an early neoplastic process. Reversible

Question 3

Baum Wk5

neoplasia

Answer 3

“new growth” – the point of no return – a cancer, whether benign or malignant

Question 4

Baum Wk5

Cancer pathway

Answer 4

Stepwise mutations results in a progression of changes –> CANCER. Ex:

Question 5

Baum Wk5

adenoma vs carcinoma

Answer 5

“oma” simply means tumor or growth. Adenoma= benign tumor growing up out of epithelial (into lumen or out onto skin for example). Carinoma= invades below the basement membrane. Epithelial and malignant. Malignancy=invasion (growing down beneath BM)

Question 6

Baum Wk5

metastasis

Answer 6

is the spread of a disease from one organ or part to another organ or part. Hallmark of malignancy

Question 7

Baum Wk5

Why do we need to understand metastasis?

Answer 7

The metastatic lesion may be the presenting lesion and be important for DIAGNOSIS The extent of disease will determine the appropriate THERAPY - surgery, chemo tx, radiation tx The extent of metastasis determines PROGNOSIS - tumor Grade (histologic) and tumor Stage (how far it has spread)

Question 8

Baum Wk5

tumor cell heterogeneity

Answer 8

• the metastatic cells are different from the primary tumor
• also, cells within the primary tumor are different from one another

Question 9

Baum Wk5

(4) Pathways of tumor spread

Answer 9

(1) Local Invasion – many types of carcinomas (2) Direct seeding - ovarian ca in peritoneum (3) Lymphatic spread - most common for carcinomas, breast ca, lung ca. Also seen with sarcomas. Lymph nodes are the first line of defense. (4) Hematogenous spread - most common for sarcomas, but also seen in renal and liver ca. Mets to liver and lung.

Question 10

Baum Wk5

(12) Steps of Tumor Invasion

Answer 10

Step 1-4: Invasion through ECM.

Step 5 - Vascular dissemination.

Step 6 - Circulation of tumor cells.

Step 7 - Attachment at a distant site.

Step 8 - Extravasation at a distant site.

Step 9 – Tumor cell attachment at a distant site.

Step 10 – Growth at a distant site.

Step 11 - Angiogenesis.

Step 12 - Evasion of the antitumor immune response.

Question 11

Baum Wk5

Steps 1-4: Invasion of ECM (4 key points)

Answer 11

1) Epithelial cells detach from eachother without undergoing apoptosis (normally prevents wandering cells. Cell has acquired mutation in suppressor genes prior to separation).
2) Adhesion to basement membrane. Cell oriented in basal direction (opposite of normal). KEY STEP: epithelial to mesenchymal transition.
3) Proteolytic dissolution of BM by proteases (matrix metalloproteinases, collagenases, etc)
4) Locomotion of cell through ECM via chemotactic factors. Realignment of ECM fibers to radiate out from tumor (like a highway along which cell travels)

Question 12

Baum Wk5

Step 5: Vascular dissemination

Answer 12

Intravasation: cell enters into blood vessels or lymph.

Highly vascular tumors have higher metastatic rates. Proximity of organs determines metastsis location

Question 13

Baum Wk5

Step 6: Detachment from endothelial cells and circulation of tumor cells

Answer 13

Ciruclation as tumor emboli after separation from endothelial cells

May be covered with other non-malignant cells such as platelets

Question 14

Baum Wk5

Step 7: Attachment to endothelium at distant site

Answer 14

Reattach to endothelium.

Certain tumor cells may recognize or attach more easily to certain tissues/organs. Uses adhesion molecules (selectins, integrins, CD44)

Question 15

Baum Wk5

Step 8: Extravasation at distant site

Answer 15

Enters into the new organ/tissue.

Paget’s seed/soil hypothesis

Question 16

Baum Wk5

Setp 9: Attachment to ECM/stromal cells at distant site

Answer 16

The milieu at the distant site Paget’s seed/soil hypothesis.

Note: Some tumors attach but cannot invade, e.g. ovarian carcinoma in the peritoneum

Question 17

Baum Wk5

Step 10: Growth at distant site

Answer 17

Tumor attempts to degrade ECM to make room for growth. Uses IL-6 to degrade surrounding tissue and as a growth factor to grow.

Note: Growth restricted to certain sites (eg cant grow in tough cartilage)

Question 18

Baum Wk5

Step 11: Angiogenesis

Answer 18

Tumor needs blood vessles to grow, and make bFGF and VEGF

Tumor vasculature may be sensitive target for chemotherapy or radiation

Question 19

Baum Wk5

Step 12: Evasion of antitumor immune response

Answer 19

Some of the tissues express death triggers, (e.g. FasL) which induces apoptosis of infiltrating cytotoxic T lymphocytes.

Also tumors can hide out in immune privileged tissues (testes, brain)

Question 20

Baum Wk5

“3-pronged” clinical approach to cancer

Answer 20

(1) Surgery: remove primary tumor. ineffective for metastasis
(2) Radiation therapy: toxic but effective for local metastasis
(3) Chemotherapy: effective but limited by bioavailability and vascular access to metastasis. Also tumors become resistant so must give many diff types

Question 21

Baum Wk5

Cancer statistics

Answer 21

-1 in 200 Americans will receive a cancer diagnosis in 2010. -2 in 5 Americans will receive a cancer diagnosis in their lifetime. -1 in 30 Americans are currently living with cancer. ~ 1500 people die each day from cancer in the U.S. -1 in 5 Americans will die of cancer

Question 22

Hallmarks of malignancy

Answer 22

Invasion and Metastasis

Question 23

What determines tumor grade?

Answer 23

Histologic abnormalities

Question 24

What determines tumor stage?

Answer 24

Extent of spread

Question 25

Paget’s seed/soil hypothesis

Answer 25

Metastatic cell has to be put in the right environment in order to grow

Question 26

Why is it important to use combinatorial approaches in cancer therapy?

Answer 26

1) tumor cell heterogeneity
2) high mutation rate

Question 27

Summary of invasion/metastasis

Answer 27

1) Detachment
2) Adhesion
3) Proteolytic dissolution
4) Locomotion
5) Intravasation
6) Detachment
7) Attachment
8) Extravasation
9) Attachment
10) Growth
11) Angiogenesis
12) Evasion of immune response