Path Book: Chapter 5 Neoplasia pg. 190-201 Flashcards
Most normal human cells have a capacity of how many replications?
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.
What does the shortening of telomeres cause at a cellular level?
- 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.
How can a cell be saved from mitotic fusion apoptosis?
activation of telomerase.
NOTE: In the time it takes for telomerase to save a cell, multiple mutations can accrue
Is telomerase normally seen in somatic cells? Stem cells?
Telomerase, active in normal stem cells, normally is absent from, or present at very low levels in, most somatic cells.
Is telomerase normally seen in cancer cells?
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.
What is one malignant cancer that telomerase expression has been linked to?
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
Would a tumor 3mm in diameter be vascularized? How do you know?
Yes, tumors cannot enlarge beyond 1 to 2 mm in diameter unless they are vascularized.
Why is 1-2mm the max diameter a tumor can grow without oxygen?
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.
How are tumors vascularized?
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
Why else is angiogenesis important for cancer tumors?
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.
What are the major inducer and inhibitor of angiogenesis in tumors?
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.
Does angiogenesis begin early in a tumor development?
No, They remain small or in situ for years until the angiogenic switch terminates this stage of vascular qui- escence.
How does hypoxia impact tumor growth and angiogenesis?
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.
Is HIF-1α active in normoxic settings? Why or why not?
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
What are the basic steps of the invasion-metastasis cascade?
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.
What layers must a carcinoma pass through to get into vasculature to disseminate?
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.
The first step in the metastatic cascade is a loosening of tumor cells. Explain how this works.
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.
The second step in invasion is local degradation of the basement membrane and interstitial connective tissue. How do tumors do dis?
Tumor cells may either secrete proteolytic enzymes themselves or induce stromal cells (e.g., fibroblasts and inflammatory cells) to elaborate proteases. Think MMPs
What is the third step in metastasis?
invasion involving changes in attachment of tumor cells to ECM proteins.
What should happen if a cell looses it’s adherence to its appropriate ECM via integrins?
Loss of adhesion in normal cells leads to induction of apoptosis, while, not surprisingly, tumor cells are resistant to this form of cell death.
How do tumor cells protect themselves from the immune system once in vasculature?
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.
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?
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.
Why would some cancer cells preferably invade certain tissues over others?
perhaps they express certain vascular adhesion molecules that predispose them to invade certain organs. This represents a possible target for therapy
T of F. Once separated from the primary tumor, cancer cells often are successful at invading and colonizing tissue
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.
