Path Book: Chapter 5 Neoplasia pg. 190-201

Question 1

Most normal human cells have a capacity of how many replications?

Answer 1

60-70. hereafter, the cells lose the capacity to divide and enter senescence. This phenomenon has been ascribed to progressive shortening of telomeres at the ends of chromosomes.

Question 2

What does the shortening of telomeres cause at a cellular level?

Answer 2

• Short telomeres seem to be recognized by the DNA repair machinery as double-stranded DNA breaks, leading to cell cycle arrest and senescence, mediated by TP53 and RB. In cells in which the checkpoints are disabled by TP53 or RB mutations, the nonhomologous end-joining pathway is activated in a last-ditch effort to save the cell, joining the shortened ends of two chromosomes.
• Such an inappropriately activated repair system results in dicentric chromosomes that are pulled apart at anaphase, resulting in new double-stranded DNA breaks. The resulting genomic instability from the repeated bridge–fusion–breakage cycles eventually produces mitotic catastrophe, characterized by massive apoptosis.

Question 3

How can a cell be saved from mitotic fusion apoptosis?

Answer 3

activation of telomerase.

NOTE: In the time it takes for telomerase to save a cell, multiple mutations can accrue

Question 4

Is telomerase normally seen in somatic cells? Stem cells?

Answer 4

Telomerase, active in normal stem cells, normally is absent from, or present at very low levels in, most somatic cells.

Question 5

Is telomerase normally seen in cancer cells?

Answer 5

By contrast, telomere maintenance is seen in virtually all types of cancers. In 85% to 95% of cancers, this is due to upregulation of the enzyme telomerase (turned back on).

Makes tumors immortal.

Question 6

What is one malignant cancer that telomerase expression has been linked to?

Answer 6

progression from colonic adenoma to colonic adenocarcinoma, early lesions had a high degree of genomic instability with low telomerase expression, whereas malignant lesions had complex karyo- types with high levels of telomerase activity

Question 7

Would a tumor 3mm in diameter be vascularized? How do you know?

Answer 7

Yes, tumors cannot enlarge beyond 1 to 2 mm in diameter unless they are vascularized.

Question 8

Why is 1-2mm the max diameter a tumor can grow without oxygen?

Answer 8

Like normal tissues, tumors require delivery of oxygen and nutrients and removal of waste products; the 1- to 2-mm zone presumably represents the maximal distance across which oxygen, nutrients, and waste can diffuse from blood vessels.

Question 9

How are tumors vascularized?

Answer 9

Cancer cells (and large benign tumors) can stimulate neoangiogenesis, during which new vessels sprout from previously existing capillaries, or, in some cases, vasculogenesis, in which endothelial cells are recruited from the bone marrow.

vasculature is abnormal and leaky

Question 10

Why else is angiogenesis important for cancer tumors?

Answer 10

Angiogenesis is required not only for continued tumor growth but also for access to the vasculature and hence for metastasis.

Angiogenesis is thus a necessary biologic correlate of neoplasia, both benign and malignant.

Question 11

What are the major inducer and inhibitor of angiogenesis in tumors?

Answer 11

The prototypical angiogenesis inducer and inhibitor are vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1), respectively. Normal p53 induces synthesis of TSP-1.

Question 12

Does angiogenesis begin early in a tumor development?

Answer 12

No, They remain small or in situ for years until the angiogenic switch terminates this stage of vascular qui- escence.

Question 13

How does hypoxia impact tumor growth and angiogenesis?

Answer 13

Relative lack of oxygen stimulates production of a variety of pro-angiogenic cytokines, such as vascular endothelial growth factor (VEGF), through activation of hypoxia-inducible factor- 1α (HIF-1α), an oxygen-sensitive transcription factor.

Question 14

Is HIF-1α active in normoxic settings? Why or why not?

Answer 14

No, it is continuously produced, but in normoxic settings the von Hippel–Lindau protein (VHL) binds to HIF-1α, leading to ubiquitination and destruction of HIF-1α.

• In hypoxic conditions, such as in a tumor that has reached a critical size, the lack of oxygen prevents HIF-1α recognition by VHL, and it is not destroyed. HIF-1α translocates to the nucleus and activates tran- scription of its target genes, such as VEGF. Because of these activities, VHL acts as a tumor suppressor gene, and germline mutations of the VHL gene are associated with renal cell cancers, pheochromocytoma, and hemangiomas of the CNS

Question 15

What are the basic steps of the invasion-metastasis cascade?

Answer 15

1) local invasion of ECM
2) intravasation into blood and lymph vessels,
3) transit through the vasculature,
4) extravasation from the vessels,
5) formation of micrometastases, and
6) growth of micrometastases into macroscopic tumors.

Question 16

What layers must a carcinoma pass through to get into vasculature to disseminate?

Answer 16

A carcinoma first must breach the underlying basement membrane, then traverse the interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular basement membrane.

This cycle is repeated when tumor cell emboli extravasate at a distant site. Thus, to metastasize, a tumor cell must cross several different basement membranes, as well as negotiate its way through at least two interstitial matrices.

Question 17

The first step in the metastatic cascade is a loosening of tumor cells. Explain how this works.

Answer 17

E-cadherins act as intercellular glues, and their cytoplasmic portions bind to β-catenin.
Adjacent E-cadherin molecules keep the cells together; in addition E-cadherin can transmit antigrowth signals by sequestering β-catenin.

E-cadherin function is lost in almost all epithelial cancers, either by mutational inactivation of E-cadherin genes, by activation of β-catenin genes, or by inap- propriate expression of the SNAIL and TWIST transcription factors, which suppress E-cadherin expression.

Question 18

The second step in invasion is local degradation of the basement membrane and interstitial connective tissue. How do tumors do dis?

Answer 18

Tumor cells may either secrete proteolytic enzymes themselves or induce stromal cells (e.g., fibroblasts and inflammatory cells) to elaborate proteases. Think MMPs

Question 19

What is the third step in metastasis?

Answer 19

invasion involving changes in attachment of tumor cells to ECM proteins.

Question 20

What should happen if a cell looses it’s adherence to its appropriate ECM via integrins?

Answer 20

Loss of adhesion in normal cells leads to induction of apoptosis, while, not surprisingly, tumor cells are resistant to this form of cell death.

Question 21

How do tumor cells protect themselves from the immune system once in vasculature?

Answer 21

some tumor cells form emboli by aggregating and adhering to circulating leukocytes, particularly platelets (forming a tumor embolus); aggregated tumor cells are thus afforded some protection from the antitumor host effector cells. Most tumor cells, however, circulate as single cells.

Question 22

The site of extravasation and the organ distribution of metastases generally can be predicted by the location of the primary tumor and its vascular or lymphatic drainage. How?

Answer 22

Many tumors metastasize to the organ that presents the first capillary bed they encounter after entering the circulation.

In many cases, however, the natural pathways of drainage do not readily explain the distribution of metastases.

Question 23

Why would some cancer cells preferably invade certain tissues over others?

Answer 23

perhaps they express certain vascular adhesion molecules that predispose them to invade certain organs. This represents a possible target for therapy

Question 24

T of F. Once separated from the primary tumor, cancer cells often are successful at invading and colonizing tissue

Answer 24

F. Despite their “cleverness” in escaping their sites of origin, tumor cells are quite inefficient in colonizing of distant organs. Millions of tumor cells are shed daily from even small tumors and the vast majority will not cause secondary cancer.

Question 25

T or F. Reprogramming of energy metabolism is common to tumors

Answer 25

T, so true that it is now considered a hallmark of cancer.

Question 26

How do tumor cells change their metabolism?

Answer 26

The Warburg effect. Even in the presence of ample oxygen, cancer cells shift their glucose metabolism away from the oxygen-hungry but efficient mitochondria to glycolysis.

Question 27

Are tumors that adopt aerobic glycolysis like Burkitt lymphoma fast growing or slow growing?

Answer 27

Fast, despite the diminished output of ATP

Question 28

In what other biological situation is aerobic glycolysis adopted?

Answer 28

In rapidly dividing normal cells, such as those in the embryo, also adopt Warburg metabolism, indicating that this mode of metabolism is favored when rapid growth is required.

Question 29

What is hereditary nonpolyposis colon carcinoma (HNPCC) syndrome?

Answer 29

This disorder, characterized by familial carcinomas of the colon affecting predominantly the cecum and proximal colon, results from defects in genes involved in DNA mismatch repair.

Remember two-hit: Each affected person inherits one defective copy of one of several DNA mismatch repair genes and acquires the second hit in colonic epithe- lial cells.

Question 30

A characteristic finding in the genome of patients with mismatch repair defects is _______.

Answer 30

microsatellite instability (MSI).

seen in about 15% of sporadic cancers

Question 31

What are microsatellites?

Answer 31

Microsatellites are tandem repeats of one to six nucleotides found throughout the genome.

In normal people, the length of these microsatellites remains constant. By contrast, in patients with HNPCC, these satellites are unstable and increase or decrease in length.

Question 32

What is Xeroderma Pigmentosum?

Answer 32

Patients with xeroderma pig- mentosum are at increased risk for the development of cancers of sun-exposed skin.

The basis for this disorder is defective DNA repair.

Ultraviolet (UV) rays in sunlight cause cross-linking of pyrimidine residues, preventing normal DNA replication. Such DNA damage is typically repaired by the nucleotide excision repair system, but not here.

Question 33

Mutations in two genes, ___ and ___ , account for 50% of cases of familial breast cancer.

Answer 33

BRCA1 and BRCA2

Question 34

In addition to breast cancer, women with BRCA1 mutations have a substantially higher risk of what?

Answer 34

Epithelial ovarian cancers.

and men have a slightly higher risk of prostate cancer.

Question 35

Cells that lack BRCA1 or 2 are characterized by what?

Answer 35

cells that lack these genes develop chromosomal breaks and severe aneuploidy. Indeed, both genes seem to function, at least in part, in the homologous recombination DNA repair pathway.

Question 36

Accumulating evidence suggests that inflammation, often thought of as a protective response against tumors, can paradoxically also enable malignancy. This occurs in two different settings:

Answer 36

1) Persistent chronic inflammation in response to microbial infections or as part of an autoimmune reaction. This is exemplified by the increased risk of cancer in patients affected by a variety of chronic inflammatory diseases of the gastrointestinal tract. These include Barrett esophagus, ulcerative colitis, Celiac, H. pylori gastritis, hepatitis B and C, Hashimoto’s, and chronic pancreatitis. As with any cause of chronic tissue injury, there is a compensatory proliferation of cells in an attempt to repair the damage. Persistent cell replication and reduced apoptosis under these conditions place the cells at risk of acquiring mutations in one or more of the genes involved in car- cinogenesis. In addition, inflammatory cells such as neutrophils can contribute to carcinogenesis by secretion of reactive oxygen species, which in turn can inflict addi- tional DNA damage in rapidly dividing cells.

• When inflammation occurs in response to tumors. Pathologists have known for quite some time that many tumors are infiltrated by leukocytes. The degree of inflammation varies, but virtually every tumor contains cells of the adaptive and innate components of the immune system. The conventional wisdom has been that the inflammatory reaction is protective since it represents an attempt by the host to destroy the tumor. Indeed, that may well be the purpose of the inflammatory reaction, but these cells can exert tumor-promoting activity by producing growth factors and inflicting additional DNA damage as described above.

Question 37

What is the significance of inflammation playing a role in carcinogenesis?

Answer 37

Anti-inflammatories like COX-2 inhibitors can be applied for therapeutic effect