3-metastasis Flashcards
steps of metastasis
- invasion
- intravasation
- transport through circulation
- extravasation
- colonization
intravasation
invasive cells penetrate the wall of the recruited vessel
extravasation
leave the vessel
the _______ is a critical player in invasion and metastasis
tumor microenvironment
the tumor microenvironment secrete factors that allow tumor cells to undergo
epithelial to mesenchymal transition
2 phases of metastasis
- physical translocation to new site
- colonization at new site
2 major strategies for invasion
- single cell dissemination
- collective migration
3 prerequisites for invasion
- cooperation of neighboring cells
- secretion of proteases to degrade ECM
- epithelial to mesenchymal transition (ECM)
how can tumor cells become invasive
- alter their adhesion molecules and receptors
- tumor cells secrete protease or factors that induce stromal cells to inc. expression and secretions of enzymes
- induce stromal cells to secrete chemokines and motility stimulatory factors that promote tumor cell migration
ecm degradation necessary for ____ and ___
invasion
migration
why do carcinoma cells go through EMT
-allow epithelial cells to transiently change their phenotype and acquire mesenchymal-like properties
what happens to epithelium during EMT
dissolution of tight junctions and adheren junctions and causes the cells to express mesenchymal markers and secrete proteases
what mediates EMT
EMT-TFs that are also responsible for the ability of carcinoma cells to degrade ECM and exhibit enhanced motility
EMT breaks
intracellular adhesions
inflammatory cells provoke
EMT
stromal cells contribute to induction of
EMT
4 pathways that a tumor can metastasize
- blood vessels
- lymphatics
- body cavities
- transplantation
angiogenesis
the process by which new blood vessels sprout from pre-existing capillaries
angiogenesis facilitates
intravasation
normal oxygen conditions, prolyl-hydroxylase promotes _______ and ________ of HIF-1a
ubiquitination
proteasomal degredation
under hypoxic conditions, prolyl-hydroxylase is ______. HIF1a is _____
inactive
not degraded
HIF-1a accumulates and _________
induces transcription of VEGF and other angiogenic factors
early stage tumors are not yet vascularized because______
the BM keeps them separate from the underlying blood vessels
once tumors breach BM, they are
vascularized
angiogenic switch refers to the transition
from a poorly vascularized, pre malignant phenotype to a highly vascularized, malignant one
factors that are responsible for “throwing” the switch
-angiogenic activators
-inhibitors
Tumor TME interactions promote ______
tumor angiogenesis
tumor cells secrete VEGF and other factors that stimulate proliferation and migration of endothelial cells but they dont reach targets___
because they are sequestered by components of ECM
VEGF does not have an effect until Matrix metalloproteinases ________
degrade ECM which release active VEGF
What cells secrete MMPs
tumor associated macrophages and mast cells
tumor cells secrete factors that ___________
recruit and activate macrophages and mast cells
macrophages and mast cells secrete other factors that ___
work in combination with VEGF to promote angiogenesis
tumor cells, local inflamm cells stimulate endothelial cell survival, activation, proliferation, and migration. ________ recruit _____ which _____
activated endothelial cells
endothelial cell progenitor cells
mature to provide additional endothelial cells for capillary sprouting
tumor vasculature
structurally and functionally abnormal
few pericytes
leaky
perfusion is variable
factors that induce invasion and angiogenesis also promote
entry into lymphatics
circulating tumor cells encounter hazards
-physical forces
-hostile microenvironment
-anchorage dependent
-tagets for NKs
circulating tumor cells arrest via :
- mechanical entrapment
- site specific arrest
2 methods that tumor cells can exit
- single cell extravasation
- intravascular growth and vessel rupture
once a tumor cell infiltrates secondary site, it has several fates:
- die
- survive in dormant state
- micrometastasis
- proliferation to form macro-metastasis
what happens when tumor cells are arrested in the vessel
endothelial cells express cell adhesion molecules (CAMs) that interact with tumor cell surface molecules
factors that affect the fate of metastatic colony
- dormancy (lack of GFs)
- rate of cell division
- angiogenesis
formation of pre-metastatic niche
-remodel ECM
-activate resident fibroblasts
-mobilize inflammatory cells from bone marrow
secondary tumor increases in size
micrometastasis
further growth and dev of the tumor (macrometastasis) requires
recruitment of blood vessels
