Exam 3 (Lecture 18) - Neoplasia 2 Flashcards
How do tumor cells avoid the cellular replication checkpoints?
Many neoplastic cells no longer respond to extrinsic or intrinsic signals directing them into G0 and no longer express functional p53.
- p53 is a multifunctional tumor suppressor gene that initiates cell cycle arrest and give the cell time to
repair DNA damage
So, the altered cells move continuously through the cell cycle even if DNA damage is present.
Since the tumor cells do not undergo cell cycle arrest to repair the DNA damage, they progressively accumulate potentially mutagenic DNA damage.
Describe the proliferative properties of neoplastic cells.
Neoplastic cells have essentially unlimited proliferative potential (a hallmark of neoplasia), especially of malignant neoplasms.
Unlike normal cells, many tumor cells are immortal.
In general, neoplastic cells:
- escape normal limits on cell division
- become independent of external growth stimulatory and inhibitory factors
- lose their responsiveness to apoptotic signals
How do cells normally die?
Cell Senescence and Death
- Senescent cells = somatic cells that can no longer divide
- these cells stop dividing through a mechanism called replicative senescence (ie permanent cell arrest)
- 220 types of somatic cells in an animal's body
- Cells can undergo a specific number of mitotic divisions before becoming senescent
- Shortening of the chromosomal telomeres with each mitotic division
- Apoptosis
- may occur in response to withdrawal of survival or growth factors from the cell environment or to
binding of death factors, such as Fas ligand and tumor necrosis factor-alpha (TNF-alpha), to cell surface
receptor
- DNA damage may also induce apoptosis
What is autophagy?
Self-eating
- Cells consume their own damaged organelles or abnormal accumulations as a housekeeping function
- Also consume cytosolic proteins and CHOs as a source of nutrients
Evolved as a cell survival mechanism during starvation, loss of trophic hormones/growth factors, hypoxia, oxidative injury, or microbial infections.
Describe the stepwise tumor development of neoplastic transformation.
1) Initiation
2) Promotion
3) Progression
Neoplasms occur as a result of the stepwise transformation of normal cells into tumor cells that are able to escape ordinary mechanisms of growth control.
What is initiation?
An irreversible alteration of genetic material.
What is promotion?
The selective outgrowth of initiated cells to form a benign tumor.
What is progression?
The gradual development of features of malignancy resulting from a combination of genetic and epigenetic changes.
Describe stepwise tumor development.
1) INITIATED cells have irreversible genetic damage
2) In the presence of a PROMOTER, these initiated cells expand to form a preneoplastic lesion or benign tumor that proliferates BUT DOES NOT INVADE THE UNDERLYING BASEMENT MEMBRANE.
3) With further genetic and epigenetic alterations, a malignant tumor emerges from a subclone of cells within the benign precursor lesion. THE MALIGNANT CELLS ARE NOW ABLE TO BREACH THE BASEMENT MEMBRANE.
Describe tumor heterogeneity and clonal selection.
1) Most tumor cells are derived from a single transformed cell.
2) Tumor cell heterogeneity is generated during tumor growth by the progressive accumulation of heritable changes in tumor cells.
3) Successful subclones have a high proliferative rate, evade the animal’s immune response, stimulate the development of an independent blood supply, and/or become independent of exogenous growth factors.
Discuss the tumor microenvironment with regards to stroma.
Tumor-stromal interactions:
- stroma = supporting tissue around cancer cells
1) A tumor consists of the neoplastic cells and nonneoplastic supporting stroma.
2) ECM, blood vessels, fibroblasts, inflammatory cells, and immune cells make up the stroma.
3) Tumor cells and their stroma exert considerable mutual control
4) Tumor cells can stimulate angiogenesis, the formation of new blood vessels, to support continued growth.
5) Likewise, the stroma can provide growth factors or immune cells that can promote tumor growth.
Discuss the tumor microenvironment with regards to angiogenesis.
Continued growth of solid tumors depends on an adequate blood supply to provide oxygen and nutrients to tumor cells.
Tumors are limited to a maximum diameter of 1-2 cm without the development of new blood vessels though angiogenesis.
At some point during tumor development, an angiogenic switch occurs that allows tumor cells to induce and sustain new tumor vasculature.
Describe the blood vessels that a tumor develops as a result of angiogenesis.
1) Vascular endothelial growth factor (VEGF) and fibroblast growth factors (FGFs) are among the most potent angiogenic factors produced by tumors.
2) The tumor blood vessels that develop in response to angiogenic signals are usually more dilated, more tortuous, and more permeable (leaky) than normal blood vessels.
- This may facilitate the spread of tumor cells and development of metastases.
- However, this vascular instability can also lead to central tissue necrosis and hemorrhage as tumor grows.
Describe the tumor microenvironment with regards to inflammation.
Tumors are often heavily infiltrated with neutrophils, eosinophils, mast cells, lymphocytes, histiocytes, or a combination of these cells.
1) Inflammatory cells are attracted to tumors by chemokine and cytokines released by tumor cells.
2) Infiltrating inflammatory cells can then recruit additional leukocytes to the tumor.
- In general, this inflammation does not seem to protect against tumors.
- Instead, these inflammatory cells serve as a source of prostaglandins, leukotrienes and reactive oxygen
species. (Procarcinogenic environment).
- Can result in DNA damage and contribute to the accumulation of mutations in the promotion phase of
carcinogenesis.
- Prolonged inflammation can be carcinogenic.
What are the cell types involved with tumor immunity?
1) Immunosurveillance cells
2) Tumor antigens
3) Antitumor effector mechanisms
4) NK cells
5) Macrophages
6) T-Cells
7) B-Cells
