Study your flashcards anywhere!

Download the official Cram app for free >

  • Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off
Reading...
Front

How to study your flashcards.

Right/Left arrow keys: Navigate between flashcards.right arrow keyleft arrow key

Up/Down arrow keys: Flip the card between the front and back.down keyup key

H key: Show hint (3rd side).h key

A key: Read text to speech.a key

image

Play button

image

Play button

image

Progress

1/98

Click to flip

98 Cards in this Set

  • Front
  • Back
hyperplasia
increased proliferation
dysplasia
morphologic abnormalities and loss of normal architecture, but without invasion
neoplasia
(“new growth”) = a cancer, whether benign or malignant
Hyperplasia and dysplasia reversible?
hyperplasia and dysplasia may be reversible, and do not always lead to cancer.
neoplasia reversible?
neoplasia is “the point of no return” – the cells are now cancerous
Distinction between benign vs malignant neoplasms
invasion and metastasis are hallmarks of malignancy.
Invasion
the tumor grows through the basement membrane, or through other tissue barriers, to locally invade surrounding tissues.
Metastasis
tumor cells detach from the primary tumor and travel via lymphatic or venous spread to other tissues, where the tumor cells multiply at distant sites.
Why is it important to understand the molecular basis of invasion and metastasis?
- determines diagnosis, therapy and prognosis – 50% of patients with solid tumors have detectable or occult mets at the time of diagnosis

- multiple therapeutic targets are required for cancer treatment, since there is significant tumor cell heterogeneity and a high mutation rate

- most conventional therapies are targeted at dividing cells, but cell division is not required for invasion and metastasis

- molecules regulating metastasis will be important therapeutic targets, as patients learn to live with cancer
- typically, invasion and metastasis are the features responsible for the lethality of cancer
Pathways of tumor spread (see below)
– direct seeding
– lymphatic spread
– hematogenous spread
Estimated % of cells in a primary tumor can metastasize
<0.01%; those cells that can metastasize have a selective advantage.
Cells that can metastasize arise when during tumor progression?
In most types of cancer, cells that can metastasize arise late in tumor progression – this is an important clinical consideration.
Mestastases similar to what in the events leading up to it?
The ability to form metastases is usually acquired in a stepwise fashion, similar to the original process of oncogenesis.
What did Robins say about neoplasms?
Think of tumor growth and spread in a manner similar to species occupying ecologic niches and surviving due to mutations conferring selective advantages.
- Robbins says “Neoplasms are essentially parasites” (pg. 319)
What do tumors need to do to survive and progress?
- cell division -- oncogenesis
- cell survival -- oncogenesis
- ability to invade
- ability to grow at a distant site
Can the metastatic cells be very different than the original transformed cell in the primary tumor? What is this called?
The metastatic cells may be very different that the original transformed cell in the primary tumor – tumor heterogeneity
Clinical approaches to cancer therapy employ three modalities
- Surgery – can remove or debulk primary tumor, but usually ineffective for metastases

- Radiation – can kill micrometastases, but limited by toxicity to surrounding tissues


- Chemotherapy – can also kill micrometastases, but limited by bioavailability and vascular access to metastases
What is radiation limited by as therapy?
limited by toxicity to surrounding tissues
What is surgery ineffective for?
metastases
What is chemotherapy limited by as therapy?
limited by bioavailability and vascular access to metastases
Therapeutic targets for controlling metastases will include what?
- anti-adhesion molecules
- protease inhibitors
- anti-growth factors
- anti-angiogenic factors
Why is it important to use combinatorial approaches in cancer therapy?
Because of tumor cell heterogeneity and high mutation rate.
What are the steps required for invasion and metastasis?
1. Detachment of tumor cells from one another

2. Adhesion to basement membrane

3. Proteolytic dissolution of the basement membrane

4. Locomotion of cells across extracellular matrix

5. Intravasation – entry into blood vessel or lymphatic

6. Detachment from endothelial cells

7. Attachment to endothelium at a distant site

8. Extravasation – leaving the blood vessel or lymphatic

9. Attachment to extracellular matrix or stromal cells at a distant site

10. Growth at the distant site

11. Angiogenesis at the distant site

12. Evasion of the immune response at distant sites
Detachment of epithelial cells typically induces what?
apoptosis; cells must first acquire mutations in tumor suppressor genes that would trigger apoptosis after detachment, then acquire mutations that permit detachment
What does E-cadherin do?
regulates apithelial cell adhesion
Is E-cadherin up or downregulated in many tumors (breast, colon, prostate)?
downregulated
What are the first 4 steps are required for local invasion as well as being the first steps in metastasis
1. Detachment of tumor cells from one another

2. Adhesion to basement membrane

3. Proteolytic dissolution of the basement membrane

4. Locomotion of cells across extracellular matrix
Adhesion to basement membrane involves what?
- polar or directional movement of tumor cells in the basal direction – the opposite direction that normal epithelial cells move

- the Epithelial – to – Mesenchymal Transition (EMT) is an essential step
What is an essential step for adhesion to basement membrane?
the Epithelial – to – Mesenchymal Transition (EMT)
Proteolytic dissolution of the basement membrane involves what?
- tumor cells make proteases to destroy the basement membrane, or induce the surrounding non-malignant fibroblasts to make proteases
- most common are metalloproteinases, including gelatinases, collagenases and stromelysins, also cathepsin D
- tumor cells also down-regulate production of endogenous protease inhibitors, such as TIMP (tissue inhibitor of metalloproteinases)
(T/F) Tumor cells can induce the surrounding non-malignant fibroblasts to make proteases
TRUE
What are the most proteases?
metalloproteinases: gelatinases, collagenases and stromelysins, also cathepsin D
(T/F) Tumor cells can down-regulate production of endogenous protease inhibitors.
True
Example of endogenous protease inhibitor that tumor cells can down-regulate the production of?
TIMP (tissue inhibitor of metalloproteinases)
Locomotion of cells across extracellular matrix involves what?
1. dissolution of ECM by proteases

2. binding to ECM by adhesion molecules and haptotactic movement along gradients of adhesion molecules

3. active chemotaxis; many of the proteolytic fragments of the ECM are chemotactic for tumor cells
(T/F) Tumor cells have increased expression of adhesion molecules such as integrins, that can bind to laminin, collagen and vitronectin in the ECM
TRUE
What can integrins bind to in the ECM?
laminin, collagen and fitronectin
(T/F) Many of the proteolytic fragments of the ECM are chemotactic for tumor cells
TRUE; many of the proteolytic fragments of the ECM are chemotactic for tumor cells
Intravasation involves entry in to either ______ or _______.
Intravasation involves entry into blood vessel or lymphatic
Epithelial tumors usually metastasize via what route?
epithelial tumors usually metastasize via LYMPHATIC route
Msenchymal tumors usually metastasize via what route?
Msenchymal tumors usually metastasize via HEMATOGENOUS (blood) route
Where do epithelial tumors typically first metastasize to?
local lymph nodes
What does the tumor need to dissolve to slip past endothelial cells
vessel basement membrane
(T/F) highly vascular tumors have a higher rate of metastasis
True
Where do mesenchymal tumors typically metastasize to?
lung
What is required for tumor cells to circulate as single cells or as tumor cell emboli?
Detachment from endothelial cells
(T/F) Tumor cell emboli may lodge in smaller vessels that drain the tumor
TRUE
Embolus formation promotes what?
tumor cell survival in the circulation – may be covered with other non-malignant cells such as platelets
Attachment to endothelium at a distant site may occur due to what?
recognition of specific adhesion molecules expressed by endothelial cells in specific organs
many tumors exploit leukocyte adhesion molecules (such as?) to bind to what?
to bind to endothelium during metastases...

adhesion molecules such E-selectin, CD44 and integrins.
Tumors express what not normally found on the non-malignant cell?
adhesion ligands
(T/F) not only patterns of drainage that determine metastases – may be organ specific homing, e.g. lung -> adrenals, breast and prostate -> bone
TRUE
How does extravasation occur (leaving the blood vessel or lymphatic)?
some tissues may secrete chemotactic factors that attract tumor cells adhering to the endothelium
How does attachment to extracellular matrix or stromal cells at a distant site occur?
- Paget – the seed/soil hypothesis

- Some tumors attach to tissues but cannot invade, e.g. ovarian carcinoma in the peritoneum
Growth at the distant site occurs as the result of what?
- Specific growth factors in different tissues; e.g. IL6 in bone marrow promotes plasma cell growth – may explain why normal and neoplastic plasma cells, which arise in lymph nodes, home to bone
- Tumor must be able to degrade surrounding tissue, as in primary site, including extracellular matrix, bone
- Some tissues are resistant to degradation, e.g. cartilage, scar tissue
What tissues are resistant to degradation?
cartilage, scar tissue
(T/F) IL6 in bone marrow promotes plasma
TRUE
Angiogenesis at the distant site occurs how?
- tumor angiogenic factors are important for metastases as well as for primary tumor growth – required for tumor growth beyond 1-2 mm diameter
- tumor cells make bFGF and VEGF
- surrounding cells make additional factors, such as TNF-alpha from macrophages
- endothelial cells begin to invade from normal vessels in surrounding tissue
- tumor endothelium is very fragile – may be excellent target for chemotherapy and radiation therapy
B/c tumor endothelium is very fragile, it is an excellent target for what?
chemotherapy and radiation therapy
(T/F) Endothelial cells begin to invade from normal vessels in surrounding tissue
TRUE
Evasion of the immune response at distant sites occurs how?
- tumors may hide out in immune privileged tissues such as testes, brain
- tumors may kill invading T cells
What are some immune privledged tissues?
testes, brain
(T/F) surrounding cells make additional factors, such as TNF-alpha from macrophages
TRUE
Tumor cells make what for angiogenesis?
bFGF and VEGF
What is required for tumor grown beyond 1-2 mm diameter?
angiogenesis
Cells can exist in what three states with regard to cell division?
- Cells that are always in the cell cycle

- Post-mitotic cells that will never divide again.

- Cells that are "resting", but can be induced by appropriate, often cell-type specific, signals to divide.
To divide, cells must do what two things?
(1) double the DNA

(2) divide it equally between two sibling cells.
(T/F) The principle biochemical characteristics of the cell cycle are conserved in all eukaryotic cells.
TRUE
What is the most easily observable portion of the “cell cycle”.
MITOSIS
What is the period between two mitoses
interphase
(T/F) Pulse labeling cells with a radioactive DNA precursor and monitoring the immediate appearance of radioactivity in the nucleus defines the S phase of the cell cycle.
TRUE
The S (or DNA synthetic) phase of the cell cycle can be defined by what when doing pulse labeling?
the sub-population of cells that incorporate a short “pulse” of a biosynthetic precursor to DNA.
(T/F) Pulse labeling cells with a radioactive DNA precursor and monitoring the appearance of radioactivity in the nucleus at times after removal of the radioactivity defines the other interphase cell cycle phases, G1 and G2.
TRUE
What is DNA content doubled and halved?
The DNA content doubles in S phase, and is halved in M phase.
The flow microflourimeter is often used to measure what?
cell cycle parameters
A flow microfluorimeter determiness what?
the content of DNA in individual cells
In nondividing tissues, most cells are arrested in a what state?
Go state.
Mitogens are agents that stimulate Go cells to ...?
enter G1 and progress around the cycle
Other specific events occur as cells go through the cycle:
Histone synthesis occurs only during S phase.

Histone phosphorylation: Histones are subject to a great deal of post-translational modification. Histone phosphorylation is greatly increased at the end of G2.

There appears to be a G2-M histone kinase activity.
Histone synthesis occurs only during what phase?
S phase
Histone phosphorylation occurs as the result of a great deal of post translation modification. When is histone phosphorylation greatly increased?
at the end of G2.
(T/F) There appears to be a G2-M histone kinase activity.
TRUE
Restriction point
When cells reach a point in the cell cycle, they must decide whether they are going to continue around the cycle, or whether they will go off into Go. This point is called the “restriction point”.
“restriction boundary protein”?

what happens phosphorylated?
A specific protein that regulates the progression through the restriction point.

The RB protein prevents transcription factors, which activate genes required to prepare the cells for the G1/S transition.

Only when RB is phosphorylated will transcription of these genes occur.
(T/F) RB must be de-phosphorylated before the replicating cell returns to the restriction point in the next cell cycle!!
TRUE
(T/F) To study events occurring in the cell cycle, we often want to synchronize cells.
True
How can one synchronize cells?
with the use of a DNA synthesis inhibitor
If we add an inhibitor of DNA synthesis, cells will accumulate where?
at the G1/S boundary and in S.
If we remove the DNA inhibitor, one can monitor the length of what?
the G2 phase, and the S phase
If we add a DNA synthesis inhibitor again after removing it, one can do what?
synchronize cells at the G1/S interface.
We can also collect mitotic cells by washing them off dishes, and replating them on new dishes. These cells will be at....
the M/G1 interphase
What controls the transitions between cell cycle phases?
Cell fusion data, creating heterokaryons, suggest regulatory activities.
(T/F) S/G1 fusions suggest that S phase cells contain an activator that can initiate DNA synthesis in G1 cells.
TRUE
(T/F) G2/G1 fusions suggest no S-phase activator is present in G2 phase cells.
True
(T/F) G2/S fusions suggest that G2 DNA (replicated DNA) does not respond to the S-phase activator.
TRUE
(T/F) G2/S fusions suggest that S phase cells have a cytoplasmic signal that delays entry into mitosis until DNA synthesis is complete and preparations for mitosis are complete.
TRUE
(T/F) M phase cell/interphase cell fusions lead to premature chromosome condensation in the interphase nucleus. This factor is called M-phase promoting factor, or MPF.
TRUE
(T/F) There exist “checkpoints” where the cell asks “are conditions right to enter DNA synthesis?” and “are conditions right to enter divide?” These are genetically controlled events. If the cell is has not appropriately replicated its DNA or the DNA is damaged, it will pause and repair the damage, or elect to initiate “apoptosis”, or programmed cell death.
TRUE