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Pathomechanismen > Metastasis > Flashcards

Metastasis Flashcards

1
Q

Tumor = Cancer?

A
  • Cancer = malignant tumor / metastasizing tumor
  • Benign tumors ≠ cancer: sometimes with the potential to become malignant

Major characteristics of a malignant tumor:
* Detachment and migration
* Destruction of tissue barriers
* Invasion into the blood and foreign tissues
* Survival and proliferation in foreign tissues

➜ Benign tumors possess 5 out of 6 hallmarks of cancer

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2
Q

Cancer metastasis

A

Primary Tumor
≈ 70% of all tumor cells are able to reach the blood vessel
≈ 60% (of these 70%) survive in the blood stream
≈ 1% (of these 60%) form a dormant micro-metastasis
≈ 1% (of this 1%) start to proliferate
“Detectable” Metastasis

Metastases are the primary cause of cancer morbidity and mortality:
-> About 90 % of the deaths due to cancer involve tumors that have spread around the body

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3
Q

Experimental models

A

Mouse models are used to investigate molecular mechanisms in cancer and metastasis:
1. Xenograft models: Human to mice -> subcutaneous of orthotropic
2. Syngeneic models: Mice to mice -> subcutaneous of orthotropic
3. chemically induced cancer mouse models subcutaneous of orthotropic
4. genetically engineered mouse models (GEMMs)

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4
Q

Classification of metastasis

A

Multiple steps are necessary to form metastasis:

Primary tumor formation -> local invasion -> intravasation -> survival in the circulation -> arrest at a distant organ site /Extravasation -> micro metastasis formation -> metastatic colonization -> clinically detectable macroscopic metastasis

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5
Q

Local invasion

A
  • Cancerous cells loose the epithelial, differentiated phenotype and gain mesenchymal cell type behavior -> enables migration
  • Characterized by profound transcriptional and epigenetic changes: loss of apico-basal polarity -> gain of mesenchymal proteins
  • Epithelial to mesenchymal transition (EMT):
  • Loss of polarity
  • Loss of cell-to-cell and cell-to-basal lamina junctions
  • Acquisition of a motile and migratory phenotype
  • Enabling the invasion of the basal lamina
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6
Q

Epithelial to mesenchymal transition (EMT)

A
  • Epithelial cells loose their cell polarity and cell-cell adhesion and gain migratory and invasive phenotype of mesenchymal cells
  • EMT is involved on physiological embryogenic development, but also recapitulated under pathological conditions, prominently in fibrosis and in metastasis of carcinomas

EPITHELIAL
- cell polarity
- cell adhesion (to each other and to extra cellular matrix)
- stationary
- high level of E-cadherin
- low level N-cadherin

MESENCHYMAL
- no cell polarity
- loss of cell adhesion
- ability to migrate and invade
- low level of E-cadherin
- high level of N-cadherin

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7
Q

Epithelial to mesenchymal transition (EMT)

A
  • EMT program is a spectrum of transitional stages between the epithelial and mesenchymal phenotypes
  • In context of metastasis:
    Epithelial cell marker: E-cadherin, cytokeratin
    Mesenchymal cell marker: N-cadherin, vimentin
  • Signaling pathways induce EMT-transcription factors (EMT-TFs) such as Twist
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8
Q

Cadherins

A
  • E-cadherins are transmembrane proteins and are important for the formation of adherens junctions
  • Cell-cell adhesion is mediated by extracellular domain
  • Intracellular cytoplasmic tail associates with numerous adaptor and signaling proteins
  • Cadherin-catenin adhesion complex: Cadherin, β-catenin and α-catenin
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9
Q

Local invasion -> loss of E-cadherins

A
  • EMT: Decrease in E-cadherins, increase in N- cadherins
  • Loss of E-cadherin expression in in vitro culture systems and in vivo in mouse models initiates EMT and enhances tumor metastasis
  • Cytoplasmic domain of E-cadherin contains a dileucine motif followed by a NVYYY motif at the membrane-proximal region
  • Src-mediated phosphorylation of the NVYYY motif induces dissociation of p120 and induces ubiquitin- ation and subsequential degradation of E-cadherin
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10
Q

p120 protein

A
  • Contains a central Armadillo repeat domain with 10 tandemly linked imperfect 42 AA repeats
  • Isoform 1: preferentially in motile cells, suggesting a role for the coiled-coil domain in cell motility
  • Isoform 3: is preferred in more sessile cells
  • p120 decreases RhoA activity and increases Rac1 activity
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11
Q

EMT-transcription factors

A
  • Extracellular signaling pathways including TGF-β, Wnt, and Notch activate EMT-inducing transcription factors (EMT-TFs) such as Snail, Slug, Twist and ZEB-1/2
  • EMT-TFs recruit various co-repressors which cooperatively repress CDH1 transcription
  • ZEB-1/2 is regulated through negative feedback loop involving microRNAs
  • CDH1 promoter is flanked by repressive histone marks like H3K9me2, H3K27me3,
    H4K20me1; loss of histone variant: H2A.Z
  • DNA methyltransferases can be recruited to the CDH1 promoter to repress gene transcription
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12
Q

Local invasion -> cytoskeletal changes

A
  • Metastasis is highly characterized by cell migration requiring dramatic remodeling of the cellular cytoskeleton (microfilaments, intermediate filaments and microtubules)
  • Epithelial cells -> polarity
  • Mesenchymal cells -> migration
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13
Q

Microfilaments -> Actin

A
  • present as a free monomer called G-actin (globular) or as part of a linear polymer micro- filament called F-actin (filamentous)
  • EMT: actin cytoskeleton is reorganized to induce the migratory phenotype
  • Ventral stress fibers: associated with focal adhesions at both ends; located on the ventral surface of the cell; function in adhesion and contraction
  • Transverse arcs: not directly linked to focal adhesions; typically flow from the leading edge of the cell, back towards the cell centre
  • Dorsal stress fibers: attach to focal adhesions on the ventral surface of the leading edge; extend towards the cell center to attach to transverse arcs
  • Actin retrograde flow: focal adhesion acts as a molecular clutch when tethers to ECM and impedes the retrograde movement of actin, thus generating the pulling force at the site of the adhesion that is necessary for the cell to move forward
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14
Q

Local invasion -> cytoskeletal changes

A
  • Intermediate filaments: switch from cytokeratin-rich to vimentin-rich networks
  • Support a dynamic nature and offer flexibility of the cell
  • Vimentin plays a significant role in supporting and anchoring the position of the organelles in the cytosol
  • Transgenic mice that lack vimentin appeared normal, but wounded mice that lack the vimentin gene heal slower than their wild type counterparts
  • Expression of vimentin is associated with poor prognosis in numerous types of cancer
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15
Q

Intravasation

A
  • Tumor cells cross the endothelial cell barrier and enter the lymphatic or blood circulation
  • Active or passive event, depending on tumor type, vessel structure and tumor environment
  • Structural differences between lymphatic and blood vessels (e.g. lymphatics do not have the tight endothelial junctions seen in blood, less flow rate in lymphatic system)
    -> entry and survival of tumor cells in lymphatic system is easier
  • Intravasation is highly correlated with tumor angiogenesis
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16
Q

Intravasation -> signaling pathways

A
  • Matrix metalloproteinases lead to the remodeling of junctions
  • Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) induce cleavage of vascular endothelial junctions
  • Angiopoietin 1 receptor (TIE2) leads to detachment of pericytes and disruption of endothelial cells
  • Macrophages can attract intravasation by secretion of EGF and TNF1α
17
Q

Survival in the circulation

A
  • After intravasation, cells are exposed to the blood flow as circulating tumor cells (CTCs)
  • CTCs are vulnerable to death induced by shear stress and turbulence
  • Interaction with immune cells leads to degradation of tumor cells
  • Less than 1 % of circulating tumor cells flowing in the blood every day will survive and have a chance to produce distant metastasis

Transit -> Arrest and adhesion -> extravasation and initial seeding -> survival and growth -> metastasis

18
Q

Interaction with natural killer cells

A
  • NK cell functions are regulated by a balance between activating and inhibitory signals
  • NK cells are able to recognize and spontaneously kill ‘stressed’ cells (e.g. infected or tumor cells) without prior sensitization
  • provides a powerful tool for use in immunotherapeutic approaches

a) healthy cells
b) missing self
c) induced self-ligands
d) ADCC

19
Q

Escaping Natural killer (NK) cells

A

Mechanisms to escape immune cells:
a) Platelets coating tumor cells can secrete immunosuppressive factors (e.g. TGFβ) and can display ligands for inhibitory receptors in order to dampen NK cell activation
b) Tumor cells can secrete immunomodulatory molecules (e.g. prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), adenosine, TGFβ and interleukin-10 (IL-10))
c) Tumor cells can shed NKG2D ligands (NKG2DLs), and these soluble ligands mask or down-modulate NKG2D on NK cells
d) Stromal cells or myeloid-derived suppressor cells (MDSCs) can secrete immunosuppressive molecules or can express NKG2DLs, which can cause a chronic interaction with NKG2D on NK cells that leads to down-modulation

NKG2D: receptor, which is expressed by all NK cells and activates NK function by ligand binding

20
Q

Survival in the circulation

A
  • Circulating tumor cells (CTCs) activate platelets by paracrine (extracellular secretion) or juxtacrine (contact-dependent signaling) signaling
  • Clotting leads to reduced shear stress and reduced interstitial flow, thereby providing docking sites for the arrest of CTCs
21
Q

Extravasation

A

To colonize distant organs, circulating tumor cells must overcome many obstacles:
- Infiltrating distant tissue
- Evading immune defenses
- Generation of and adapting to supportive niches
- Surviving as latent tumor-initiating seeds
- Breaking out to replace the host tissue
- Surviving cancer therapy

Vessel structure differs between tissues:
- Continuous: skin, muscles, lung, CNS -> TIGHT
- Fenestrated: exocrine glands, renal glomeruli, intestinal mucosa
- Discontinuous: liver, spleen, bone marrow -> LEAKY

  • Permeability is influenced by endothelial cells and pericytes
  • Vessel structure might influence where a tumor might extravasate
22
Q

Adhesion

A
  • RAC1 (RhoGTPase): switch between a round and elongated phenotype
  • Early attachment and rolling of cancer cells:
    • interaction of endothelial selectin (E-selectin) with its ligands sialyl Lewis (sLea/sLex)
    • neuronal cadherin (N-cadherin) homophilic interactions
  • Stable adhesion of cancer cells to ECs depends on integrins, CD44 and/or mucin 1 (MUC1)
23
Q

Adhesion

A
  • RAC1 (RhoGTPase): switch between a round and elongated phenotype
  • Early attachment and rolling of cancer cells:
    • interaction of endothelial selectin (E-selectin) with its ligands sialyl Lewis (sLea/sLex)
    • neuronal cadherin (N-cadherin) homophilic interactions
  • Stable adhesion of cancer cells to ECs depends on integrins, CD44 and/or mucin 1 (MUC1)
24
Q

Rho GTPases

A
  • critical role in regulating cell migration, intra- and extravasation
  • Rac, Rho and Cdc42 family signaling and the associated deregulation of cell motility and invasion is a hallmark of cancer metastasis ➜ governing mesenchymal cell motility
  • molecular switch between inactive GDP-bound and active GTP-bound state mediated by guanine nucleotide exchange factors (GEFs) and GTPase-Activating Proteins (GAPs)
  • Actomyosin contraction: Rho/ROCK, Cdc42/MRCK
  • Directionality: Cdc42/Par complex, Microtubules
  • Filopodia: Cdc42/mDia
  • Lamellipadia: Rac/WAVE complex, Rho/mDia
  • adhesions to extracellular matrix: Rac/PAK, Rho/ROCK
25
Q

GEFs

A
  • Tiam1-mediated Rac1 activation enhances Rac1 binding to IQGAP1
  • Reduced IQGAP1-b-catenin binding ➜ formation of stable α-catenin-β-catenin-E-cadherin complexes ➜ stronger adherens junctions ➜ reduced cell migration
  • P-Rex1 activates Rac1 while enhancing its interaction with FLII
  • increased phosphorylation of MLC and activation of myosin II ➜ stimulation of myosin II leads to increased actomyosin contractility and ECM remodeling ➜ cell migration
26
Q

Arrest at distant organ sites - Extravasation

A

Chemokine receptor induced tissue tropism:
* Chemokine receptors are important for attraction-based cell migration
* Breast cancer cells express chemokine receptor 4 (CXCR4) on their surface
* Circulating breast cancer cells are arrested in vascular beds in organs that produce high levels of CXCR4 ligand (CXCL12)
* Binding of CXCL12 to CXCR4 induces the migration of cancer cells into normal tissue
* Breast cancer cells do not usually metastasize to organs that produce low levels of CXCL12 (such as kidney)

27
Q

“Seed and soil” theory

A
  • primary tumor can promote metastasis by inducing the formation of a supportive microenvironment ➜ premetastatic niche
  • pro-metastatic tumor cells (“seed”) colonize in specific organ sites (“soil”)

a) Single-organ PMN formation with monoclonal metastasis
b) Multiple-organ PMN formation with organ-specific monoclonal metastasis
c) Multiple and organ-specific PMN formation with monoclonal or polyclonal metastasis

28
Q

Pre-metastastic niche -> Establishment

A

Establishment of the pre-metastatic niche (PMN):
- Vascular leakiness: Clot formation and increased micro vessels permeability
-> vascular endothelial growth factor (VEGFA)
-> Angiopoietin-like 4 (ANGPTL4)
-> Focal adhesion kinase (FAK)
- local increase in cytokines like chemokine C-C motif ligand 2 (CCL2) correlates with the recruitment of various bone marrow-derived cell populations
- clotting by platelets promote initiation of coagulation and clot formation by tissue factors (TF)

29
Q

Pre-metastastic niche -> Evolution

A

Evolution of the pre-metastatic niche (PMN):
* Extracellular matrix (ECM) is actively deposited and remodelled
- Accumulation of fibronectin (FN) and crosslinking of collagen I (via lysyl oxidase (LOX))
- Secretion of matrix metalloproteinases (MMPs)
* Inflammatory cell recruitment
- Transforming growth factor-β (TGFβ)-dependent production of proteins such as periostin
- Upregulation of S100 proteins generates inflammation and recruitment of haematopoietic progenitor cells and differentiated immune cells

30
Q

Tumor dormancy and cancer stem cells

A
  • Cancer dormancy is a stage in tumor progression in which residual disease remains asymptomatic for a prolonged period of time (> 5 years)
  • Quiescence is the state where cells reside in G0–G1 arrest
  • Cancer stem cells (CSCs) may be responsible for the continued growth, invasion, and metastasis of tumors, and resistance to various used chemitherapeutic treatments
  1. oncogene inactivation
  2. lack of angiogenic switch
  3. lack of growth stimulation
  4. host polymorphisms imposing growth delay
  5. proliferation inhibition
  6. need for additional genomic alterations
  7. aberrations in adhesion factor signalling
  8. immunological factors
31
Q

Tumor dormancy and cancer stem cells -> signaling most likely comes from the microenvironment

A
  • hereditary host factors: Sipa1
  • microenvironment epithelial-stomal cross-talk: CXCL-12
  • growth stimulatory factors: EGFR/uPAR pathway, ERK and p38 pathway -> proliferation switch
  • oncogenes and metastasis suppressor genes: MYC and HER2 up regulation, nm23-H1 and KISS1 down regulation -> AGGRESSIVE POTENTIAL
  • phenotypic characteristics: Ki-67 (down regulation), EMMPRIN (up regulation), CD44+/CD24, CK19+/MUC1- -> PROLIFERATION MARKER
  • immunological factors: CD274 (down regulation), HLA class I antigene (up regulation)
  • angiogenic factors: HIF1alpha and VEGF up regulation -> ANGIOGENIC SWITCH
  • Switch between proliferation and dormancy: mitogenic signaling from Ras-extracellular signal-regulated kinase (ERK) pathway, and stress induced signaling from p38 pathway
    ➜ Higher ERK/p38 ratio indicates proliferation and a lower ratio causes dormancy
32
Q

From micro- to macrometastasis

A
  • Single extravasated tumor cells proliferate to form “pre-micrometastases” in which cells lacked contact with neighboring tumor cells and are active and motile
  • Cells from micrometastasis undergo mesenchymal to epithelial transition (MET) and loose the ability to migrate
  • Molecular mechanisms in MET are rarely elucidated
33
Q

Micrometastasis formation

A
  • Micrometastasis are too small to be seen with imaging tests
  • Micrometastasis can be only visualized by microscopy
  • typical biopsy procedure involves staining of specific markers that correspond to the particular tumor type
  • Micrometastases are crucial in choosing treatment options
    ➜ Most micro-metastatic tumor cells are in the non-proliferative G0 phase
    ➜ Adjuvant chemotherapy and adjuvant radiation are more effective to eliminate micrometastases
34
Q

Warburg effect

A
  • Cellular phenomenon in cancer cells discovered by Otto Warburg in 1924
  • Cancer tissue consumed 10x more glucose than accounted for respiration
  • Produced 100x more lactic acid than in normal tissue
    -> Cancerous cells preferentially use aerobic glycolysis for energy production rather than oxidative phosphorylation
    -> cancer cells metabolize glucose, using pathways that generate less energy (ATP) per glucose molecule consumed
35
Q

Warburg effect - Advantage or side effect?

A
  • Damaged mitochondria -> BUT: several studies demonstrated healthy mitochondria
  • Hypoxia -> BUT: the Warburg effect is also present in cancer cells with normoxia
  • Greater energy yields than oxidative phosphorylation by greatly increasing glycolysis
  • Large amount of glycolytic products for intermediates in biosynthetic pathways
36
Q

Clinical significance of PK-M2

A
  • Transfer of phosphate group from phosphoenolpyruvate to ADP yielding ATP and pyruvate
  • PK-M2 can occur in two different forms:
  • a tetrameric form, which consists of four subunits
  • a dimeric form, consisting of two subunits (Tumor M2-PK)
  • Tumor PK-M2: predominant in proliferating cells and upregulated in many human tumors
37
Q

Role of PK-M2 in Warburg effect

A
  • Tetrameric form of M2-PK has high affinity to its substrate, phosphoenolpyruvate
  • Due to close proximity to enzymes within the glycolytic enzyme complex conversion of glucose to pyruvate is highly effective
  • Dimeric form of M2-PK has low affinity for phosphoenolpyruvate
  • Phosphometabolites accumulate and are channeled into synthetic processes
  • Energy is produced by catabolism of glutamine to generate ATP and lactate which is termed glutaminolysis ➜ 6 ATP
38
Q

Fluorodeoxyglucose

A
  • Warburg effect leads to up-regulation of glucose transporters (e.g. GLUT1 and GLUT3)
  • Radiopharmaceutical glucose analoges can be used in the medical imaging modality positron emission tomography
  • 2-deoxy-2-[18F]fluoroglucose ([18F]FDG): glucose analog with the radioactive isotope fluorine-18 substituted for the normal hydroxyl group at the C-2 position in the glucose molecule
  • 2-hydroxyl group is needed for glycolysis thus [18F]FDG cannot be metabolized before radioactive decay
  • Phosphorylation to [18F]FDG-6-phosphate can not be exported
    -> [18F]FDG-6-phosphate accumulates in the cell
  • 80% of the 18F activity remains in tissues and is eliminated with a half-life of 110 min by decaying in place to Oxygen-18 to form non-radioactive [18O]O-glucose-6- phosphate
  • 20% of total 18F activity is eliminated renally by 2 h with a rapid half-life of about 16 minà renal-collecting system and bladder prominent in a normal PET scan
  • FDG-PET/CT is frequently used to assess tumor therapy progress

Pathomechanismen (13 decks)

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