Lecture 5 - Metastasis (Naba) Flashcards
What is metastasis and where does it occur in cancer progession?
Metastasis is the process by which a tumor cell leaves the primary tumor, travels to a distant site via the circulation, and establishes a secondary tumor.
- considered to be the last step in cancer progression
Dissemination routes
- Hematogenous spread: cells invade bloodstream
- Lymphatic spread ( breast cancer route)
- Spread into body cavaties
- Transplantation: spread by surgery tools using a diagnostic surgery
Hypothesis for metastatic trophism
- certain tumors disseminate preferentially to certain organs
- hypothesis: mechanistic theory: determined by pattern of blood flow
- seed and soil: migrate to a favorable environment with lots of GFs and ECM
models of dissemination
- linear model
- early dissemination w parallel evolution of primary tumor -> different tumors have different mutations
- Late dissemination from primary from single subclone -> secondary tumor is one subtype of the primary
- late dissemination from multiple subclones within primary -> secondary tumors are all different
Seeding is a COMPLEX process and results in diversity within the pool of metastasis
The metastatic cascade
- Primary tumor adhesion: 2 types, either adhere to cell matrix or to each other via gap junctions
- Cell dissociation and EMT
- Invasion out of epithealial cell
- Intravasation into bloodstream
- Circulation
- Extravasation
- Colonization in target organ.
- Each step requires tumor to gain new abilities thru altered gene expression
- tumors interact w stromal cells at every step
Steps
- Remodelling of cellular adhesions
- Motility and invasion
- Intravasation
- survival in circulation
- extravasation
- seeding and survival in distal site: microenv becomes important
- Metastatic outgrowth
EMT
- epith to mesenchymal phenotype, cells gain ability to migrate.
- reversible
- use invadopodia: action rich protrusions and sites of local ECM degradation
Intravasation
- this is physiologically normal in immune cells. cancer cells use many of same mechs
- traverse BM
- stromal cells (macs) can promote by leading tumor cells to vessel
Survival in circulation
- cancer cells must acquire the ability to survive without a matrix to attach to
- CTCs circulating tumor cells experience stress, pressure and friction in the vessel
- also need to avoid the immune system -> platelets coat the cancer cells
- most tumor cells dont survive this process
CTCs in diagnostics
- attempt to isolate and study CTCs
- # of CDCs is a prognostic indicator, monitor cancer progression
- tool for personalized medicine
Arrest
- selectins play a role
- cells tether, slow roll, adhere and then exit bloodstream
Extravasation
- recruits macrophages to help ID opening (Metastatic associated macrophages)
- exits through barrier opening
Dormancy
Disseminated tumor cells can remain dormant in distal sites for years
We dont know what awakens them
- may be an intrinsic model OR may be due to microenv of tumor.
- may be not enough nutrients or oxygen
CSCs and metastasis
tumor growth is feuled by small fraction of dedicated stem cells.
Tumor Microenvironment
- different TAM at different stages of tumor
- the ECM has different niches
- tumors need: angiogenesis in order to disseminate, macrophages to destabilize endo barrier
- liver, brain, lung metastasis all have unique cellular components that come together to support metastasis. Different needs in different niches.
- There are different therapeutic strategies that target components of the micro env. (ex anti vasc, anti immune, anti cell recruitment)
