AMC-HC 7: Invasion & Metastasis Flashcards
13-02
When are most tumors noticed?
When they start influencing the function of organs and tissues
Tumor metastasizing potential differs per tissue. Which cancer has a high risk for metastasis? And which have a lower risk?
Melanomas – high
Basal cell carcinomas of skin and astrocytomas – low
Stages of metastases
Intravasation
> Transport through cicrulation
> Arrest in microvessels of various organs
> Extravasation
> Formation micrometastasis
> Formation Macrometastasis
For carcinomas, the most common cancers, to invade, they need to break through the basement membrane. Which enzymes help them?
Proteases that cleave the ECM > malignant cells locally invade nearby tissues and gain access to growth factors and blood supply of the stromal niche
Which action increases the risk of metastasis enormously?
Breaking through the basement membrane
How do macrophages enable intravasation of cancer cells into the circulation?
They secrete EGF > stimulation intravasation
Why is the blood a hostile environment for cancer cells?
-No support from stroma cells
-No contact with other cells
-Hydrodynamic shear stress in vessels
-Not built for microcapillaries (they have large nuclei and do not fit well.
A readout for risk for metastasis (useful for therapy), is made by measuring …
Circulating tumor cells (CTCs)
What is a problem with measuring CTCs?
Complicated comparisons between cancers and patients
Detection of tumor DNA
Mutation profile: mutations and translocations
Most CTCs spend little time in cicrulation. Where do they end up? and can they escape this place?
They get stuck in the lung microcapillaries > but they can escape and get stuck nearby other organs in the systemic circuit and metastase there.
What characteristic of cancer cells is essential for metastasis?
Their size: they have to get stuck in microcapillaries to be able to invade
Mechanisms of extravasation by cancer cells
-Through the endothelium
-Growing within the vessel
When cancer cells escape from vessels, they enter a new environment with growth factors and new stroma cells et cetera. Does this have a positive or negative effect on the cancer cell?
Can be either positive or negative
Colonizing cancer cells first form micrometastases. From which number of micrometastasis, a macrometastase is formed?
There is no vast number > the chance of forming a macrometastasis is very low
Why is the chance of formation of micrometastasis very low?
The new environment is not compatible to a single cancer cells most of the times.
The incedence of micrometastases has a negative effect on the patients …
prognosis
Differences between initial micrometastases and secondary wave
-Initial micrometastases: generically distinct: cells can disseminate but not colonize > different mutagenic profiles (selection, only the best adapted cells will be able to form micrometastases and macro)
-Secondary wave: generically similar, derived from the primary metastasis which was adapted well to the colonization of new tissues.
Secondary wave of metastases is also called the …. and is responsible for the …
Metastatic shower > most deaths (faster growth because of better adaptation)
Micrometastases will die after a few days if they do not grow, true/false?
False: they can remain dormant for large periods of time > waiting for colonization
Which transition enables invasion?
Epithelial-mesenchymal transition (EMT)
What do carcinoma cells need to do to acquire motility and invasiveness?
-Shed epithelial phenotypes, detach from epithelial sheets
-Undergo the epithelial–mesenchymal transition (EMT)
EMT is also required for normal healthy processes. Name one
Embryogenesis or wound healing response
> Carcinomas can thus activate the latent program which is usually confined to early embryogenesis and to damaged adult tissues!
> the TF’s for EMT induction are relevant
EMT involves changing of shape, acquisition of motility and fundamental alterations in gene expression. Name EMT related gene regulations
-Downregulation of E-cadherin and cytokeratins (hallmarks of epithelial cells)
-Upregulation of vimentin (large intermediate filament component of the mesenchymal cell cytoskeleton)
-Twist gene > stimulates EMT: lower expression of epithelial markers E-cadherin, beta-catenin, and gamma-catenin and higher mesenchymal marker expression: fibronectin and vimentin
E-cadherin role
Transmembrane protein: the extracellular domain functions as a hook which can links cells with E-cadherin to each other > the intracellular domains are tethered to the actin fibers of the cytoskeleton via an complex of alfa/beta-catenins. The actin cytoskeleton provides tensile strength.
Loss of E-cadherin
Beta-catenin goes free into the cytosol and translocates to the nucleus to promote proliferation genes via binding to TF’s (Wnt signaling)
> also, connectivity between adjacent cells decreases.
Which signaling is involved in EMT induction?
Paracrine / autocrine
How can tumor associated macrophages promote EMT in cancer cells?
By secreting TNF-alfa or EGF
Is EMT a reversible process?
Yes, after colonization, cancer cells can undergo a mesenchymal-epithelial transition (MET)
EMT transcription factors can also induce a special state of cells. Which one?
Stem cell state: needed for cancer cells to grow and metastasize.
> EMT program can enable carcinoma cells to translocate from the core of primary tumor to foreign tissue during metastasis
Why is stemness important for carcinoma cells?
It endows disseminating carcinoma cells to be able to form metastases and to grow.
Why are extracellular proteases important for invasion?
Remodeling of nearby tissue > excavating passageways through ECM and breaking the basement membrane
Which extracellular proteases excavate the ECM?
Matrix metalloproteinases (MMPs like MMP2)
> these proteases are secreted by macrophages, mast cells and fibroblasts.
How is the activity of MMPs normally controlled?
By the secretion of inactive pro-enzymes but in cancer, the proteolysis is a continuous process.
Which kind of expression of MMPs can drive carcinogenesis?
Ectopic expression of MMPs
What is a marker of metastasis?
Cancer cell positive lymph nodes
The site of metastasis has a certain risk per type of primary tumor. Which metastases mostly occur with prostate cancer? And with breast cancer?
Prostate: to bone marrow
Breast cancer: to lungs and bone marrow
What is the affinity of different primary tumors /cancers towards a certain organs for metastasis called?
Tropisms to these organs
Why do tropisms exist?
Because cancer cells are uniquely equipped for colonizing different sites (ability to colonize certain organs is rarely achieved)
Seed and soil hypothesis
metastizing cancer cells (seeds) find compatible home only in certain hospitable tissues (soil)
What is another factor (besides certain cancer being equipped better for metastasis in certain organs) for tropisms (preference for metastasis tissue)?
The layout of vessels and the route of cancer cells through the curculation
What sites can attract certain cancer cells?
Sites of chronic inflammation > more blood flow towards the inflammation site > blood flow patterns may explain metastase patterns
Tumor self-seeding
Tropism towards the site of the primary tumor
Vascular ZIP code (adres) theory
receptors on the walls of capillaries attract circulating tumor cells
Prediction of metastase sites:
66% (majority): blood flow patterns
20% specialized microenvironments of target tissues
14% by negative interactions > tissues actively repelling cancer cells
Why do micrometastases reduce the long-term survival of patients?
-Dormant micrometastases are often non-cycling and thus resistant to therapy
Why do immunosuppressed patients have explosive development of aggresive metastatic disease?
The immune system may suppress the growth of micrometastases
What proves the genetic determinants of metastases?
Only a subpopulations of genetic diversity of primary tumor found in metastases, so selection-based
