GP 20 - Pathology of Neoplasia 2

Question 1

What are the four phases of tumor growth?

Answer 1

1. Carcinogenesis - transformation of a normal cell to a malignant one
2. Growth of malignant cell, angiogenesis, progression, and heterogeneity
3. Local invasion
4. Distant metastases

Question 2

How many cells do human tumors usually originate from? How is this known?

Answer 2

A single transformed cell

This is established by examining G6PD isoforms. In neoplasia, there is only one. In hyperplasia, there are several

Question 3

What are the cardinal features of a transformed cell? How can these feaures be medically inhibited?

Answer 3

• Autonomous - self sufficiency in growth signals - EGFR Inhibitors
• Resistance to growth inhibitory signals - cdk inhibitors
• Resistance to apoptosis - Proapoptotic BH3 mimetics
• Genomic instability (defective DNA repair) - PARP inhibitors
• Limitless replicative potential - Telomerase Inhibitors
• Activating invaston and metastasis - HGF/c-Met inhibitors
• Inducing Angiogenesis - VEGF inhibitors
• Evasion of immunoserveillance - anti CTLA4 mAb
• Deregulation of cellular energetics - aerobic glycolysis inhibitors
• Tumor-promoting inflammation - Anti-inflammatory drugs

Question 4

How do most transformed cells achieve self sufficiency in growth signals?

Answer 4

Gain of function mutations in protooncogenes/oncogenes to produce oncoproteins which somehow stimulate cell growth

Question 5

How do most transformed cells achieve resistance to growth inhibitory signals?

Answer 5

Through loss of function mutations to both copies of one of the following tumor supressor genes:

• Rb
• TP53
• TGFβ
• APC

Question 6

How do most transformed cells achieve resistance to apoptosis?

Answer 6

Mostly through inhibition of the intrinsic (mitochondrial) pathway but also via the extrinsic pathway as well:

• p53 loss of function mutation
• Overexpression of the p53 inhibitor, MDM2
• Overexpression of anti-apoptotic members of the BCL2 family
  
  • BCL2
  • BCL-XL
  • MCL1

Question 7

How do most transformed cells achieve limitless replicative potential (immortality)?

Answer 7

Normal mature cells lack expression of telomerase, resulting in the shortening of telomeres with each replication and eventually leading to senescence. Tumor cells reactivate telomerase, thus staving off mitotic catastrophe and achieving immortality

Question 8

What is Warburg metabolism and what causes it?

Answer 8

Warburg metabolism is the name given to the phenomenon that malignant cells tend to favor glycolysis over oxidative phosphorylation.

This type of metabolism is induced by the presence of the RAS and/or MYC oncoproteins or by mutated growth factor receptors.

Question 9

Describe the importance of autophagy in tumor growth

Answer 9

During nutrient deficiency, cells cannibalize their own organelles as carbon sources for energy production (autophagy). If they remain in this state, the cell will die.

Cancer cells never enter this state of autophagy and can sustain their growth on marginal conditions

Question 10

What are oncometabolites?

Answer 10

Some oncoproteins (e.g. - mutated isocitrate dehydrogenase) cause formation of high levels of abnormal metabolites (oncometabolites) which leads to epigenetic changes and oncogenic gene expression.

Question 11

Describe how the inflammatory response to a tumor can actually help lead to malignancy.

Answer 11

• Increased protease presence leads to removal of growth suppressors. It also aids in tumor invasion by remodeling the ECM
• Factors from tumor-associated macrophages enhance resistance to cell death
• VEGF from inflammatory cells causes angiogenesis
• The increased presence of TGFβ promotes EMT (epithelial-mesenchymal transition), a key even in the process of invastion and metastasis

Question 12

Describe what tumor growth fraction is and why it’s clinically important.

Answer 12

Tumors cells have the same cell cycle phases as normal cells, including the G0 phase. This means some tumor cells are not actively proliferating. A tumors growth fraction is the proportion of cycling cells in the tumor.

Tumors with high growth fractions are susceptible to chemotherapy

Question 13

When is a tumor clinically detectable? When is it usually lethal?

Answer 13

A tumor is detectable once it reaches a volume of 1cm³. This occurs at about 10⁸- 10⁹ cells our 30 doubling from a single cell (not including cell loss)

Ten doublings past this stage yields a lethal tumor

They have to be found early

Question 14

What is tumor heterogeneity?

Answer 14

With time tumors develop new subpopulations of cells that may vary in:

• Antigenicity
• Invasiveness
• Metastatic Potential
• Growth Factor Requirement

Question 15

What are the phases of metastasis?

Answer 15

• Invasion of ECM
• Movement through the interstitial tissue
• Vascular dissemination and homing of tumor cells

Question 16

Describe how tumor cells usually manage to invade the ECM and migrate through interstitial tissues.

Answer 16

• Malignant tumor cells reduce their expression of E-Cadherin which allows them to detach from cells around them
• Malignant tumor cells begin excreting collagnease and cathepsin B which will degrade ECM proteins allowing the cells to move
• Malignant tumor cells will begin attaching to certain ECM protein components to aid in movement - laminin receptors, integrins, and new sites secreted by the tumor cells (MMP2 and MMP9).
• Autocrine motility factors (cleavage products of collagen and IGF) then stimulate the tumor cell movement through the interstitium

Question 17

What do we need to know about vascular dissemination and homing of tumor cells during metastasis?

Answer 17

• It starts with intravasation, eroding throught the wall of lymphatics of blood vessels
• Can spread as a single cell or form a multi-cell embolus with platelets and WBCs before extravasation occurs (exiting the blood vessel/lyphatic)
• The homing of tumor cells to a metastatic site depends upon the presence/absence of chemokines, other specific molecules, and favorability of the environment (usually not muscle)
• In the new metastatic site, the tumor cells will grow and stimulate angiogenesis

Question 18

What is tumor dormancy?

Answer 18

The phenomenon that primary tumors will sometimes not metastisize for for a very long time

Question 19

List the tumor antigens we need to know that the immune system can recognize.

Answer 19

• Mutated oncogene/tumor suppressor gene products - RAS, BCR-ABL
• Aberrantly expressed cellular proteins - PSA
• Antigens produced by virus - HPV, EBV
• Oncofetal antigens - CEA
• Altered Cell Surface Proteins - CA125, CA19.9 (ovarian CA)
• Differentiation Antigens - CD10 (CALLA) in B cell lymphocytes

Question 20

What are some of the bodies antitumor defense mechanisms? Which one is most prominent?

Answer 20

• Cytotoxic T lymphocytes - main mechanism
• NK Cells - direct killing and antibody dependent cell mediated cytotoxicity (ADCC)
• Macrophages (TNF/Free radicals)
• Humoral destruction by complement

Question 21

What is an immune checkpoint?

Answer 21

Immune checkpoints are regulators of the immune system designed to prevent the immune system from attacking cells indiscriminately.

Question 22

In general, how can tumor cells manage to evade the immune response?

Answer 22

By breaking down the immunological barrier:

• anitgenic modulation
• outgrowth of antigen negative clones
• increased production of CTL inhibiting proteins, which work by activating immune checkpoints (thereby inhibiting the immune system)

Question 23

Briefly describe the two mechanisms by which researchers are attempting to prevent immune checkpoint activation during tumor growth.

Answer 23

1. The CTLA4 receptor on a CD8+ T cell acts as an immune checkpoint when bound by the B7 co-receptor of a dendritic cell. Blocking the CTLA4 allows the B7 co-receptor to bind the T cell at a different receptor and cause T cell activation
2. The PD1 receptor on a CD8+ CTL by the PD1 ligand on a tumor cell acts as an immune checkpoint. Blockage of the PD1 receptor allows for CD8+ CTL activation

Question 24

What is the purpose of giving cancers grades and stages?

Answer 24

• Treatment decisions
• Determination of prognosis
• Research purposes

Question 25

Facts to know about how cancers are graded.

Answer 25

• Grading methods are specific to the tumor type, however, it is based upon the level of differentiation of the tumor cells
• Problems
  
  • variation of histology in various areas
  • observer variation

Question 26

What is cancer stagins based upon?

Answer 26

Staging is based on 3 three primary characteristics, each of which is assigned a letter.

• T - size of the primary tumor
  
  • ranging from T1 (3cm or less) to T4 (>7cm)
• N - extent of spread to regional lymph nodes
  
  • ranging from N0 (no spread) to N1, N2, or N3 (each a different area)
• M - presence or absence of metastasis
  
  • M1a, M1b, and M1c (each a different area and number of metastases)