Neoplasia Part 4, UTHSC Fall 2022 D2 Pathology

Neoplasia Part 4, UTHSC Fall 2022 D2 Pathology Resisting Cell Death or Evasion of Programmed Cell Death - Cell death by apoptosis as a protective response to several pathologic conditions that might contribute to malignancy if the cells remained viable. - Biochemical pathways leading to apoptosis - Cancer cells present mutations in the genes that regulate apoptosis What three interrelated factors are critical to the immortality of cancer cells? - Self-renewal - Evasion of senescence - Evasion of mitotic crisis A single cell can Replicate itself, or differentiate into many cell types what are the two hypotheses for cancer formation from a stem cell 1. multiple mutations of a stem cell cause it to become a cancer stem cell, leading to tumor progression 2. stem cells differentiate into a mature cell, then p53 is mutated which turns it into a cancer stem cell, leading to tumor progression Telomere A region of repetitive nucleotide sequences at each end of a chromosome Telomere Shortening and Aging as cells replication some of the repetitive sequence in the telomere is cut off. Over years this eventually causes the breakdown of cellular DNA and aging effects how do cancer cells overcome the Mitotic Catastrophe Caused by Telomere Shortening? they reactive their telomerase, which adds more length to their telomeres, extending their life Angiogenesis the process of vessel sprout from previously existing capillaries how do tumors create angiogenesis? tumors release specific factors capable of stimulating the growth of blood vessels what did Dr. Judah Folkman () show? even if a solid tumor possesses all the genetic aberrations that are required for malignant transformation, it cannot enlarge beyond 1 to 2 mm in diameter unless it has the capacity to induce angiogenesis what triggers angiogenesis? hypoxia what growth factor is transcribed to fascilitate angiogenesis? VEGF what controls angiogenesis? a balance between angiogenesis promoters and inhibitors T/F Early in tumor development, most human tumors do not induce angiogenesis True vascular quiescence stage early stage of cancer where tumors do not induce angiogenesis what terminates the vascular quiescence stage? angiogenic switch T/F Angiogenic factors such as VEGF (vascular endothelial growth factor) may be produced by tumoral cells, or by inflammatory cells (e.g. macrophages), or other stromal cells associated with the tumors True how can angiogenesis inhibitors be used to treat cancer? treatment with angiogenesis inhibitors causes the vessel supplying tumors to regress. This lack of nutrients then causes the tumor to shrink we know cancer can cause angiogenesis. Can it cause lymphangiogenesis as well? Yes, research in tumors created in mouse tongues show a marked increase in lymphatic vessels in the cancerous tongues when compared to healthy tongues Invasion and Metastasis the results of complex interactions between cancer cells and normal stroma what are the steps of cancerous growth? 1. Normal skin/ mucosa 2. Hyperplasia 3. Hyperplasia with epithelial dysplasia 4. Invasive carcinoma (Squamous cell carcinoma) Sequence of Events in the Invasion of Epithelial Basement Membrane by Tumor Cells A. Loosening of intercellular junctions B. Degradation of ECM by Type IV collagenases and Matrix metalloproteinases C. Migration and invasion The Metastatic Cascade 1. Clonal expansion, Growth, angiogenesis 2. Metastatic subclone 3. Adhesion to and Invasion of basement membrane 4. Passage through extracellular matrix 5. Intravasation 6. Interaction with host lymphoid cells 7. Tumor cell embolus 8. Adhesion to basement membrane 9. Extravasation 10. Metastatic deposit 11. Angiogenesis 12. Growth Molecular Basis of Multistep Carcinogenesis - Multiple mutations act in complementary ways to produce a fully malignant tumor. - Driver mutations and passenger mutations - How many mutations does to take to establish a fully malignant tumor? - Colon carcinoma as a classic example showing incremental acquisition of the malignant phenotype Adenocarcinoma Development of the Colon is a good example of what? How Cancer Formation Involves Multiple Mutations and Steps Carcinogenesis is a (single step/multistep) process multistep