Chapter 24: Cancer Development and Disease Flashcards
Mechanisms of Carcinogenesis
Somatic mutation theory
the idea that proliferation of a mutated cell that has become autonomous induces carcinogenesis and metastasis
mechanisms of carcinogenesis
Tissue organization field theory (TDFT)
the theory that cancer results from defective communication between mesenchymal and epithelial tissue.
-Cells naturally want to move and replicated, and this growth (statis) process is controlled via communication and contact with neighboring cells. The loss of communication allows cells to revert to its state of migrating and proliferating, resulting in tumor formation.
4 ways malignancy happens
1) context-dependent tumors
2) cell to cell communication loss
3) defects in paracrine pathways
4) cancer stem cell hypothesis
in context-dependent tumor growth, cells with normal genomes are provided the opportunity to become malignant because of their:
environment.
teratocarcinomas use the mechanisms of
context-dependent tumors
explain the mechanism of teratocarcinomas. How does environment dictate malignancy? (it is a context-dependent tumor)
they are tumors of germ cells or stem cells that resemble the inner cell mass of a mammallian blastocytes. they are deadly in adults. the malignant cells secrete PARACRINE FACTORS such as NODAL to support their proliferation and to provide the necessary vasculature for cell and tumor survival, INHIBITING APOPTOSIS.
environment dictates malignancy: when malignant cells are placed in an environment of embryonic stem cells (which secrete nodal inhibitors), aggressive neural crest cell tumors become normal pigment tumors: they down regulate their nodal expression and migrate as non-malignant cells along the neural crest cell pathways.
how does cell to cell communication loss result in tumor formation? Example?
tumors can arise when the environment around a certain group of cells stops functioning properly, resulting in poor communication.
tumors can arise when the structure of the tissue is altered, but these tumors can be suppressed by restoring an appropriate environment.
Example; epithelial cell cancers often arise from defects in mesenchymal stromal cells, surrounding the epithelia. The mesenchymal cells is what provides the cues and structure for epithelial layers.
tumors can arise from improper paracrine signalling between cells. For examples, when ___ pathways, like SHH, notch, wnt, BMP etc) become activated in adult tissues through ___ ___ or other mechanisms.
tumors can arise from improper paracrine signalling between cells. For examples, when EMBRYONIC pathways, like SHH, notch, wnt, BMP etc) become activated in adult tissues through SPORADIC MUTATION or other mechanisms.
many tumors secrete SHH, which either: (and give examples)
1) stimulate cells that produce it to grow via AUTOCRINE MECHANISM creating tumors (ex/ leukemia. SHH inhibitors have proven effective in treating medulloblastomas and leukemias)
2) SHH produced by the tumor can act on MESENCHYMAL CELLS around it rather than tumor cells, making them produce factors to support tumor development. A treatment is cyclopamine, which blocks SHH signaling to cause tumor regression– can’t be used on someone who is prergnant though (causes midline malformation)
Paracrine factor disregulation:
Explain how SHH produced by tumor can act on mesenchymal cells
- this graph shows that there is evidence that the stroma reulgates the production of epithelial tumors.
VEH= vehicle/placebo
Nmu = carcinogen
- applying nmu to the tumor epithelium cells doesn’t do anything, but applying Nmu to the stromal/mesenchymal cells underneath the epidermis can cause epithelial cells to become cancerous.
- reflects the fact that the pre-tumor cells can produce SHH, which act on other cells arounf it to start producing factors that support tumor development.
NOTE:
SHH, notch, Wnt, BMPs/TGFb/Activin are involved in processes essential to the proper development of an embryo but are also involved in tumerogenesis. Ex/ nodal (a tgfB) secretion by melanoma cells
two mechanisms behind SHH tumerogenesis
1) autocrine mechanisms (B)
- SHH stimulates the sae cell it is produced from, emabling it to grow. Seen in small cell lung carcinoma, pancreatic adenocarcinoma, prostate cancer, breast cancer.
2) paracrine mechanism
- SHH secreted by one cell exerts effects on stomal cells, causing the stromal cells to produce factors (like IGF) to support the tumor cells
recall: SHH mechanism: SHH binds, and smoothened no longer gets degraded; it is free to get phosphorylated, alloing Ci to activate gene expression
In normal situations, what is autocrine SHH good for?
normally required for maintenance of cerebellar granule neuron progenitor cells, hematopoietic stem cells.
Explain how CSCs create their own niche (support cells)
cancer cells divide to form other cancer cells as well as their support cells. the differentiated cells within the tumor can secrete paracrine and juxtacrine factors (wnts, notch) that are required for further CSC growth. The niche cells can differentiate into blood vessels and endothelial cells to create tumor vasculature.
example of using differentiation therapy in acute promyelocytic leukemia
in APL, these APL cells secrete TFs that repress RA-responsive genes, and creates a condensed chromatin structure. Theese genes can now no longer make the APL cells nutrophils, and the APL cells thus stay in precursor state with no differentiation.
with RA-responsive genes being repressed since RA expression is reduced due to APL TFs, you can actually induce differentiation by GIVING RA, inducing the RA-responsive genes, making the APL cells turn into nutrophisl.
Explain the cascade for differentiation therapy in APL (leukemia).
Rogue cancer cells produce TFs, preventing RA production. Without RA, IKKalpha cannot be expressed because the inhibitory pathway prevents gene expression.
If RA IS present, it inhibits the inhibitory pathways (EED, ZUZIZ, ZHZ), releasing it from the gene, and allowing IKKalpha to be expressed, promoting differentiation
____ maintain the tissue function and integrity, and are often down regulated in tumors. How do they do this?
miRNAs. miRNA insertions are promising means of differentiation therapy. MiRNA’s are often tumor suppressors that prevent changes in DNA methylation.
in tumors, many cell types de-differentiate, entering a proliferative stage. this is usually accompanied by loss of specific miRNA’s that usually maintain the differentiated cells DNA methylation patterns. Restoring those miRNA’s tot tumor cell re-establishes the differentiated pattern of DNA methylation
