Invasion and Metastasis Flashcards
Do benign tumor invade?
no
do benign tumors metastasize?
no
invasion
the infiltration of adjacent tissue by malignant cells
metastasis
the transfer of malignant cells from the primary site to a non-connected (secondary) site. So metastases are tumors discontinuous with the primary tumor
in situ
epithelial cancers that display the cytologicla features of maligancy without invasion of the bm
demarcation of malignant tumors?
malignant tumors are poorly demarcated from the surrounding normal tissue. Tumor protruding into surrounding tissue in a crablike fashion - hence the name cancer
methods of cancer dissemination - 3 pathways
- direct seeding of body cavities or surfaces (e.g. ovarian)
- lymphatic
- hematogenous
the metastatic cascade (4)
invasion through BM and ECM
Intravasation - getting into blood / lymph
Extravasation - getting out of vessel at new site
Colonization - ability to grow at new site
Why do cancer cells metastasize?
in the primary tumor, it becomes advantageous to move beyond the BM when conditions get crowded and harsh and hypoxia limits blood and nutrients - then there is a selective pressure to move out or metastasize
emerging hallmarks (nextgen) of cancer (4)
deregulation of cellular energetics (modify metabolism)
evade immunological destruction
tumor promoting inflammation
genome instability
strong positive relationship between primary tumor size and
risk of developing metastasis
intravasation
gaining access to the circulation by penetrating the vascular BM
Invasion of the ECM is an active process that can be resolved into 4 steps
- changes “loosening” of tumor cell-cell interactions (e-cadherin loss)
- degradation of ECM
- Attachment to ECM components
- migration
What happens when tumor cells reach distant site?
extravasate
Step 1 in invasion -
dissociation of cell from one another - alterations in adhesion molecules (E-Cadherin)
what links e-cadherins to cytoskeletin?
catenins
after dissociation of cells from each other, what is the next step in invasion?
local degradation of the BM and interstitial CT
- Tumor cells secrete MMPs
How do MMPs regulate tumor invasion? (2)
- remodeling insoluble components of the basement membrane
- releasing ECM sequestering growth factors - cleavage products of collagen and proteoglycans have chemotactic, angiogenic, and growth promoting effects
In addition to degradation of ECM by MMP, what is another mode of invasion for cancer cells?
In vivo imaging shows that tumor cells can adopt a 2nd mode of invasion, termed ameboid migration - in which cells squeeze through spaces in teh matrix instead of cutting through it (using proteases)
amoeboid migration -
speed?
railways?
quicker
collagen fibers
why might amoboid movement explain the disappointing performance of MMP inibitors in clinical trials?
tumor cells can switch between the two forms of migration
once the tumor cells have detached and degraded the BM, what happens next?
step 3 = changes in attachment of the tumor cells to ECM proteins
–> normal epithelial cells have receptors, such as integrins, for BM laminin and collagens that are at their basal surface; these receptors help to maintain the cells in a resting, differentiated state - loss of adhesion in normal cells leads to induction of apoptosis (anoikis or death by detachment)
No surprisingly, tumor cells are resistant to this form of death
Additionally, the matrix itself is modified in ways that promote invasion and metastasis - for example, cleavage of the BM proteins collagen IV and laminin by MMP2 and 9 generate novel sites that bind to receptors on tumor cells and stimulate migration
The last step in invasion (after the tumor cells have loosened, secreted ECM degradation shit, and loosened their attachment to the ECM) what happens?
LOCOMOTION
propels tumor cells through the degraded BM and zones of matrix proteolysis - migration is a complex, multistep process involving families of receptors and signaling proteins that impinge on the actin cytoskeleton
cells must attach to the matrix at the leading edge, detach from teh matrix at the trailing edge, and contract the actin cytoskeleton to ratchet forward
Tumor cell movements?
movement can be potenitated and directed by tumor cell-derived cytokines
in addition, cleavage products of matrix components (collagen, laminin) and some GFs have chemotatic activity for tumor cells
proteolytic cleavage can liberate GFs bound to matrix molecules
stromal cells also produce paracrine effectors of cell motility
Loss of E-cadherin is often associated with invasive phenotype - 4 ways E-cadherin expression can be lost
- LOH
- Inactivating mutation
- silencing via hypermethylation
- transcriptional repressors
Transcriptional factors SNAIL, TWIST, and ZEB1/2 promote epithelial to mesenchymal transition (EMT) by?
repressing E-cadherin
by repressing E-cadherin, transcriptional factors SNAIL, TWIST, and ZEB1/2 do what?
promote epithelial to mesenchymal transition
What happens to E-Cadherin when ZEB1 is expressed?
it is repressed
Is epithelial to mesenchymal transition normal?
Not in adult,
it is a normal process during development that gets used inappropriately by cancer cells
Where in the metastatic cascade is the epithelial to mesenchymal transition thought to be necessary?
when they are intravasating and travelling through the circulation - can re-establish epithelial type characteristic upon recolonization
Change associated with EMT
Upregulation?
Downregulation?
UP = mesenchymal proteins
DOWN = epithelial proteins (E-cadherin / cytokeratins)
Do all EMT changes always occur and are they reversible
no they don’t all always occur and yes they are reversible
What markers do circulating tumor cells express?
you can see that they become more mesenchymal - the more mesenchymal markers usually worse outcome
What elements of the tumor microenvironment influence tumorigenesis? (3)
- mesoderm derived cells
- fibroblasts
- adipocytes
- immune cells
- endothelial cells - ECM
- collagen, etc. - Soluble and matrix associated growth factors, cytokines, proteases
what are tumor associated fibroblasts?
fibroblasts that exhibit altered expression of ECM molecules, proteases, protease inhibitors, and various growth factors
once in the circulation, tumor cells are vulnerable to destruction by (3)
- mechanical shear stress
- apoptosis stimulated by loss of adhesion (anoikis)
- immune defenses
anoikis
apoptosis stimulated by loss of adhesion
what may enhance tumor cell survival in circulation?
in the circulation, tumor cells can aggregate in clumps. Adhesion between tumor cells and blood cells, particularly platelets, may enhance tumor cell survival and implantability -
how can tuor cells cause emboli?
tumor cells can bind activate coagulation factors - resulting in the formation of emboli
macrophages and tumor cell intravasation?
macrophages can actually assist tumor cells in intravasation (getting into the vessels)
Extravasation -
site at which circulating tumor cells leave the capillaries can be due to the anatomic location of the primary tumor (1st capillary bed available) However, the natural pathways of drainage do not fully explain the distribution of metastasis
Where does prostate cancer preferentially spread to?
bone - which is not first capillary bed
Where do bronchogenic carcinomas tend to spread?
adrenals and brain
where do neuroblastomas tend to spread?
live and bones
two main theories to explain organ tropism of cancer metastatis?
- seed and soil
2. mechanical arrest
seed and soil theory of organ tropism
explained by needs of cancer cell (seed) for a specific environment (soil) to initiate and maintain growth
Ewing’s mechanical arrest theory
proposed that cells mechanically arrest in teh first capillary bed first encountered
first step in extravasation?
adhesion to the endothelium - tumor cells express adhesion molecules and the endothelial cells of the target organ express ligands for the adhesion molecules -
chemokines role in extravasation?
cancer cells can express chemokine receptors and the tissues that the cancer cells metastasize to express the chemokine - some target organs may liberate chemoattractants that recruit tumor cells to the site such as IGF1 and 2
example of well vascularized tissue that is unfavorable for metastasis?
skeletal muscle
are tumor cells efficient in colonizing distant organs?
no
dormancy ??
prolonged survival of micrometastases without progression - is well described in melanoma and breast / prostate cancer
pattern of colonization?
tumor cells secrete cytokines, growth factors, and ECM molecules that act on stromal cells, which in turn make the metastatic site habitable for the cancer cell
ultmate effect of metastases?
direct?
invasive masses which interefere with normal fx
ultimate effect of metastases?
indirect?
paraneoplastic syndrome - paracrine/endocrine effects occur in 7-15% of patients with cancer
Causes of death (top 5)
infection organ failure thromboembolism hemorrhage emaciation
