Invasion and Metastasis Flashcards
Which of the following is a cadherin function?
a. Mediating calcium-dependent homotypic cell-cell adhesion
b. Trigger apoptosis
c. Formation of intercellular junctions
d. All of the above
e. a and c
E) A and C
Lymphangiogenesis is driven by:
a) Immune cells in the lymph nodes
b) VEGF-A
c) VEGF-C
d) Lymphostatin
e) Thrombospondin
c) VEGF-C
Reversal of EMT is required for:
a) Increased cancer cell migration
b) Colonization of a secondary organ
c) Intravasation into the blood or lymph vessels
d) Reducing E-cadherin expression
e) None of the above
b) colonization of a secondary organ
What is the process of hematogenous metastasis
- Transformation
- Angiogenesis
- Motility and invasion
- Embolism and circulation.
- Arrest in capillary beds
- Adherence to cessel wall
- Extravasation into organ parenchyma
- Response to microenvironment and proliferation
- Angiogenesis, metastasis
what are the 5 major steps of metastasis
- Invasion and infiltration of surrounding normal host tissue
- Release of neoplastic cells
- Survival in circulation (only a small % of circulating cancer cells will form metastases)
- Arrest in capillary beds of distant organs
- Penetration of the lymphatic or blood vessel wall followed by growth of the disseminated tumor cells
What changes occur during cell detachment and invasion of stroma at the primary tumor site
Matrix-degrading proteinases and growth factors/receptors increase, while adhesion molecules and proteinase inhibitors decrease
What changes take place during intravasation leading to migration
Endothelial cell adhesion molecules increase as the process progresses
What factors are involved in the process of extravasation at the primary tumor site
Selection ligands, integrins, and matrix-degrading proteinases play roles in the extravasation process
What occurs during the establishment of metastases at secondary organ sites
There’s an interation with the local microenvironment, and cell-cell adhesion molecules and autocrine/paracrine growth regulatory factors increase to support metastatic growth
What methods are employed in vivo models for metastasis research?
In vivo models involve analyzing surgical biopsies from multiple organs, utilizing analyses sich as histopathology, genome, transcriptome, proteome, methylome, RAsec and scRNAseq
what are the types of animal tumor models used in metastasis research
it include spontaneous metastasis (from primary site), experimental metastasis (injecting cancer cells directly into metastatic site) and transgenic/knockout/knockin mice models (GEMM)
How are human tumor xenografts studieed in metastasis research
Human tumor xenografts and PDX (patient derived xenografts) are utilized as in vivo models for studying metastasis
How is the concept of liquid biopsy involved in in vivo models
Circulating tumor cells (CTC) are studied as part of liquid biopsy approaches in invivo models
What types of cells are utilized in invitro models for metastasis research
In vitro models include normal transformes and malignant cell lines, genetically altered cells and PDX/organoids (3 model)/slies
What reconstitued structures are used in invitro models for metastasis research
In vitro models involve reconstitued tissues such as vessel, extracellular matric models, and genetically modified cells for studying metastasis
True or false: 80% of metastasis are cancer related mortality
False, 90%
What characterizes Carcinoma in Situ in tumor cell invasion
It represents the initial step in tumor cell invasion, characterized by hyperplasia and loss of polarity but without invasion as the basement membrane remains intact
What mediates the microinvasion of tumor cells
Basement membrane degradation occurs through collagenase IV enzymes, specifically MMP2 and MMP9
What defines the initialstate of epithelial cells in their attachment to the basement membrane
They are non-migratory, possess apical-basal polarity, and attach to type IV collagen using integrins. E-Cadherin is expressed in this state
What characterizes the transition from epithelial to mesenchymal cells in EMT?
EMT involves the downregulations of E-Cadherin (holding cells together) and epithelial integrins, while upregulating N-Cadherin, mesenchymal integrins and vimentin, enabling cell motility
How do migratory cells differ from their original state
Migratory cells become spindle-shaped, lose cell junctions, change polarity, and migrate along a fibronectin matrix, upregulating integrins to attach to the matric
What distinguished homophilic from hetephilic interaction
Homophile = involve cells interacting with similar cells
Heterophilic = cells interact with other mediated by selectins
Where is Neural (N)-cadherin primarily found?
N-cadherin is present on neurons, muscle cells, and endothelial cells
Which tissues predominantly exhibit epithelial (E)-cadherin
E-Cadherin is prominently present in epithelial tissues
What is the primary location of Placental (P)-cadherins
Placenta
Where can (R)-cadherin be found
Retina
What cells typically express endothelial (EV)-cadherin (Cad 5)?
vascular endothelial cells
What is key function of classical cadherins
They mediate calcium-dependent homotypic cell-cell adhesion
What role do classical cadherins play during embryogenesis
They mediate cell sorting
What structures do classical cadherins help form
They help in forming intercellular junctions such as adheren junctions, gap junctions, tight junction and desmosomes
How do classical cadherins contribute to cellular function
They assist in establishing cell polarity and can inhibit apoptosis while regulating growth factor receptors
How maney domains does E-Cadherin contain?
E-cadherin has five domains
Ehat is the role of the transmembrane domain in cadherins
The transmembrane domain anchors the cadherin to the cell membrane
Name the intercellular molecules that the intercellular domain of integrin binds to
Beta-catenin and p120 are intercellular molecules that link the intercellular domain of integrin
Explain the function of CAD-HAV domain
The CAD-HAV domain binds the two cadherins drom adjacent cells contributing to cell-cell adhesions
How do well-differentiated, poorly invasive adenomas differ from invasive carcinoma in terms of E-Cadherin expression
Adenomas express high E-Cadherin levels, while invasive carcinomas have reduced E-Cadherin levels due to transcriptional repression, inactivation, DNA methylation, mutations, or post-transcriptional event
How can E-cadherin levels and stability of the E-cadherin-catenin complex be deregulated
Phosphorylation of E-cadherin, beta-catenin, or p120 catenin by activated receptor tyrosine kinsaes can regulate E-Cadherin levels and the stability of its complex
What are the three classes of molecules present in the ECM
Consists of structural proteins (collagen, elastins),
protein-polysaccharide complexes (proteoglycans) and
adhesive glycoproteins (fibronctins, laminins)
How many alpha and beta subunits do integrins have, and what do they form
Integrins possess 24 alpha subunits and 9 beta subunits forming multiple non-covalently bound heterodimeric transmembrane receptors
What are the four main groups into which integrins are classified
Laminin (alpha6beta4)
RGD (switch from laminin to RGD during EMT)
Collagen (mainly alpha-2-beta-2, whitch to a5-b1 for EMT)
Leukocyte-specific groups
How do RTK or chemokine receptirs affect integrin receptors
Activation of RTK or chemokine receptors causes elongation and seperation between alpha and beta subunits, allowing accessory proteins to bind to the beta subunit and recruit more proteins to initiate downstream signalling
How do integrins associate with RTKs to impact cellular functions
Integrins associate with RTKs to amplify survival and growth signals, such as alphaV beta3 with IR, VEGR, and PDGFR or alpha-5-beta1 with EGFR
How are RTKs involved in metastasis and cancer progression
RTKs can mediate EMT and contribut to different stages of metastasis
What is unique about the insulin receptor family amond RTKs
They are expressed as dimers and do not require a ligand to bind for dimerization
How does the FGF receptor relate to cancer treatments targeting the EGF receptors
The FGF receptor provides an alternative receptor when cells are treated with inhibitors of the EGF receptor leading to the failure of certain cancer treatments
Why is the VEGF receptor important in cancer
It plays a crucial role in angiogenesis and lymphangiogenesis, essential processes in tumor growth and spread
What is the role of TF snail 1 and Snail 2 (slug) in EMT
They are key regulators of the EMT program, linking Wnt, TGF-beta, and Notch signaling, activating LEF-1, MMP, and fibronectin while repressing E-cadherin
How is NF-kB linked to EMT
NF-kB, an inflammatory mediator, upregulates Snail, contributing to the EMT process
What signaling pathways regulate EMT
GSK-3B
TGF-beta
and SMAD pathways
What does GSK-3beta do?
destabilized beta-catenin, SMAD, Notch1, and Snail1 ; inhibiting EMT
What does TGF-beta do
induces EMT by activating SMAD complexes,
can cause GSK-3B inhibition,
inducer of SMAD 2/3:SMAD4 complexe causing transcriptional activation of SNAIL 1/2, E-cadherin
Also inducer of immune suppression - making the macrophages M2 be pro-tumor, neutrophil N2 are pro-tumor growth, T cells become Treg and Th2
What is the significance of E-N Cadherin switching in cancers
E-N cadherin switching, a late event in many cancers, influences cellular activities by increasing detachment, motility, survival, and growth
True or false: there a 20X increase in Snail 1 in patients with metastatic vs non metastatic HCC (liver cancer)
true
What is observed in clinical specimens regarding cadherin expression in various malignancies
Clinical specimens exhibit the presence or inappropriate cadherins, including N-cadherin, acress different malignancies
What happens when non-metastatic carcinoma cells (MCF-7) overexpress N-Cadherin
Overexpression of N-cadherin in non-metastatic carcinoma cells cause them to become metastatic
How does silencing N-Cadherin affect pancreatic carcinoma cells
Silencing N-cadherin in pancreatic carcinoma cells lead to a non-onvasive and non-metastatic phenotype
What are the outcomes of transgenic expression of N-cadherin in mammary carcinoma models
Transgenic expression of N-Cadherin does not induce tumorigenesis nor alter tumor onset in mammary carcinoma models
What conclusion can be drawn regarding Cadherin switching from these findings
Cadherin switching is identified as a late event, not directly oncogenic, but pivotal in promoting invasion and metastasis
What are the mechanisms involved in individual-cell migration
Individual-cell migration involves pseudopod protrusion for tration, recruitment of proteinases to degrade the matrix and actomyosin contraction for movement
How does collective cell migration differ from individual-cell migration
Collective cell migration employs similar mechanisms as individual-cell migration but involved coordinated movement of groups of cells
Describe the process of tumor cell invasion through tissues
Tumor cells navigate through tissue compartments, locally degrading the ECM with secreted enzymes, disrupting tissue architecture, invading nearby blood vessels and spreading to distant sites
What are MMPs dependent on in terms of their enzymatic activity
MMPs are zinc- and calcium- dependent enzymes
What role do MMPs play in normal physiological conditions
They are physiologic mediators of matrix degradation
How is the expression of MMPs regulated in the body
MMP expression is tightly controlled in the body
What characterizes the structure homology among MMPs
MMPs share a high degree of structural homology but significantly differ in substrate specificity
How are MMPs classified based on their action
MMPs are classified as collagenases, gelatinases, stromelysins, MT-MMPs, and others
What significant role do MMPs play in cancer progression
MMPs have a critical role in invasion and metastasis
What are some inhibitors of MMPs
EDTA and o-phenanthroline are inhibitors of MMPs
How many gene products of MMPs are there in humans, what unique feature does MMP9 possess
There are 23 gene productof of MMPs in human, with MMP9 pssessing a type V collagen-like domain
How are MMPs regulated in the body
MMPs are tightly regulated by gene expression, activation, inhibition, proteolytic cascades, and feedback mechanisms
What triggers the activation of MMPs from their inactive state
MMPs are inactive when secreted but become active upon cleavage of their pro-domain chemically or by displacement though another proteinase
What impart do MMPs have on metastasis and angiogenesis?
MMPs contribute to reduced metastasis and angiogenesis
What specific roles do MT-MMPs plau?
MT-MMPs directly degrade the extrecellular matric, activate pro-MMPs and de-shed from the membrane
How is MMP4 involved in breast cancer progression
MMP4 in breast cancer, is involved in vessel dissociation and intravasation, thereby increasing metastasis
What have the phenotypes of MMP-deficient mice confirmed regarding MMP’s role in cancer
Phenotypes of MMP deficient mice confirm MMP’s significant role in carcinogenesis, and metastasis
What findings emerged from studies using MMP-2 knockout mice?
Studie using MMP2 KO mice showed suppression of experimentally induced pancreatic carcinogenesis, angiogenesis and delayed mammary gland differentiation, along with mild growth retardation
What effects were observed in studies using MMP9 KO mice
MMP9 KO mice exhibited suppression of experimentally induced skin and pancreas carcinogenesis, as well as decreased experimental metastasis
What outcomes were noted in studies involving MMP11 KO mice
MMP11 KO mice displayed suppression of experimentally induced mammary carcinogenesis, reduced tumor cell survival and growth
How did MMP14 KO mice repond in studies
MMP14 KO mice showed reduced collagen turnover and defective angiogenesis
What defines invadopodia and their role in cancer cell invasion
Invadipodia are actin-rich plasma membrane protrusions linked to extracellular matric degration, crucial for cancer cell invasion and metastasis
What initiates the formation of invadopodia and what stabilizes them
Integrin binding intiates their formation, while MT1-MMP recruitment stabilizes invadipodia
What indicators mark the presence of invadopodia
F-actin, MMP9, Cortactin and degraded gelatin serve as indicators of invadopodia
What is ADAM and its role in cellular signaling
ADAM (a disintegrin and metalloproteinase) disrupts integrin signaling; ADAM10 degrades E-cadherin, while ADAM17 activated amphiregulin and TNF-alpha
What is ADAMT and where is it predominantly found
ADAMT (a disintegrin and metalloproteinase with thrombospondin motids) is predominantly secreted
What are exmaples of inhibitors of MMPs found in plasma
Alpha-2-macroglobulin,
Alpha-1-proteinase inhibitor
Alpha-1-chymotripsin
Alpha-2-antiplasmin
What are TIMPs and hoe do they act on MMPs
Tissue inhibitors of metalloproteinases (TIMPs) are highly speciific inhibitors produced by tumor or host cells, binding to and inhibiting MMPs regionnaly
What is the role of ECM collagen in angiogenesis
Certain collagens, when cleaved upon protein lysis, produce angiostatic inhibitors in the NC1 domain, such as Endostatin (Collagen XVIII), tumstatin (Collagen IV), Vastatin (collagen VIII) and restin (collagen XV)
What is a common site of metastasis for prostate cancer
Metastasize in bone
In what organ does uveal melanoma commonly metastasize
Uveal melanoma primarily metastasize to the liver
What role do chemokines play in tumor cell movement
Chemokines guide tumor cells toward specific target organs by attracting cells expressing chemokines receptors
Which chemokine is specific to lymph nodes
CCL20 is expressed in lymp nodes
What happens when tumor cells reach the site of metastasis
Tumo cells attach to vascular endothelial layers, release proteins, degrade the ECM, and experience increased proliferation
What is the outcome of enhanced cell motility in metastasis
Enhanced motility allows cells to traverse the matric and reach the target organ where they proliferate
How do tumor cells interact with platelets and neutrophils in blood
Tumor cells form microthrombi with patelets and neutrophils offereing protection and acting as a source of growth factors
What role do microthrombi play in metastasis
Microthrombi protect tumor cells and serve as source of growth factors like TGF-beta and PDGF
Which cells are unique to the liver and interact with tumor cells during early liver metastasis
Hepatic stellate cells are unique to the liver and interact with tumor cells in the early stages of liver metastasis
What interaction occur during the activation of fibrosis in the liver
Tumor cells undergo adhesion, diapedesis, and interact with hepatic stellate cells, leading to dibrosis activation and angiogenesis
Which cell procede tumor ells to the lung, establishing a pre-metastatic niche
Bone marrow cells precede tumor cells and establish a pre-metastastix niche in the lung
What role do exosomes play in the pre-metastatic niche
Exosomes from pancreatic cells induce a pre-metastatic niche in the liver before tumor cell arrival
What happes when tumor cells enter a dormant state
Some tumor cells enter a dormant state, transitioning from mesenchymal to epithelial state
What is crucial for establishing liver metastases
Re-expression of Type IV Collagen is crucial for establishing liver metastases
Why is addressing metastasis challenging
Metastasis is a dynamic process requiring different targeted therapeutic approaches for different stages
