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Final > Invasion and Metastasis > Flashcards

Invasion and Metastasis Flashcards

1
Q

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

A

E) A and C

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2
Q

Lymphangiogenesis is driven by:
a) Immune cells in the lymph nodes
b) VEGF-A
c) VEGF-C
d) Lymphostatin
e) Thrombospondin

A

c) VEGF-C

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3
Q

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

A

b) colonization of a secondary organ

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4
Q

What is the process of hematogenous metastasis

A
  1. Transformation
  2. Angiogenesis
  3. Motility and invasion
  4. Embolism and circulation.
  5. Arrest in capillary beds
  6. Adherence to cessel wall
  7. Extravasation into organ parenchyma
  8. Response to microenvironment and proliferation
  9. Angiogenesis, metastasis
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5
Q

what are the 5 major steps of metastasis

A
  1. Invasion and infiltration of surrounding normal host tissue
  2. Release of neoplastic cells
  3. Survival in circulation (only a small % of circulating cancer cells will form metastases)
  4. Arrest in capillary beds of distant organs
  5. Penetration of the lymphatic or blood vessel wall followed by growth of the disseminated tumor cells
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6
Q

What changes occur during cell detachment and invasion of stroma at the primary tumor site

A

Matrix-degrading proteinases and growth factors/receptors increase, while adhesion molecules and proteinase inhibitors decrease

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7
Q

What changes take place during intravasation leading to migration

A

Endothelial cell adhesion molecules increase as the process progresses

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8
Q

What factors are involved in the process of extravasation at the primary tumor site

A

Selection ligands, integrins, and matrix-degrading proteinases play roles in the extravasation process

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9
Q

What occurs during the establishment of metastases at secondary organ sites

A

There’s an interation with the local microenvironment, and cell-cell adhesion molecules and autocrine/paracrine growth regulatory factors increase to support metastatic growth

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10
Q

What methods are employed in vivo models for metastasis research?

A

In vivo models involve analyzing surgical biopsies from multiple organs, utilizing analyses sich as histopathology, genome, transcriptome, proteome, methylome, RAsec and scRNAseq

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11
Q

what are the types of animal tumor models used in metastasis research

A

it include spontaneous metastasis (from primary site), experimental metastasis (injecting cancer cells directly into metastatic site) and transgenic/knockout/knockin mice models (GEMM)

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12
Q

How are human tumor xenografts studieed in metastasis research

A

Human tumor xenografts and PDX (patient derived xenografts) are utilized as in vivo models for studying metastasis

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13
Q

How is the concept of liquid biopsy involved in in vivo models

A

Circulating tumor cells (CTC) are studied as part of liquid biopsy approaches in invivo models

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14
Q

What types of cells are utilized in invitro models for metastasis research

A

In vitro models include normal transformes and malignant cell lines, genetically altered cells and PDX/organoids (3 model)/slies

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15
Q

What reconstitued structures are used in invitro models for metastasis research

A

In vitro models involve reconstitued tissues such as vessel, extracellular matric models, and genetically modified cells for studying metastasis

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16
Q

True or false: 80% of metastasis are cancer related mortality

A

False, 90%

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17
Q

What characterizes Carcinoma in Situ in tumor cell invasion

A

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

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18
Q

What mediates the microinvasion of tumor cells

A

Basement membrane degradation occurs through collagenase IV enzymes, specifically MMP2 and MMP9

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19
Q

What defines the initialstate of epithelial cells in their attachment to the basement membrane

A

They are non-migratory, possess apical-basal polarity, and attach to type IV collagen using integrins. E-Cadherin is expressed in this state

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20
Q

What characterizes the transition from epithelial to mesenchymal cells in EMT?

A

EMT involves the downregulations of E-Cadherin (holding cells together) and epithelial integrins, while upregulating N-Cadherin, mesenchymal integrins and vimentin, enabling cell motility

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21
Q

How do migratory cells differ from their original state

A

Migratory cells become spindle-shaped, lose cell junctions, change polarity, and migrate along a fibronectin matrix, upregulating integrins to attach to the matric

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22
Q

What distinguished homophilic from hetephilic interaction

A

Homophile = involve cells interacting with similar cells
Heterophilic = cells interact with other mediated by selectins

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23
Q

Where is Neural (N)-cadherin primarily found?

A

N-cadherin is present on neurons, muscle cells, and endothelial cells

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24
Q

Which tissues predominantly exhibit epithelial (E)-cadherin

A

E-Cadherin is prominently present in epithelial tissues

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25
Q

What is the primary location of Placental (P)-cadherins

A

Placenta

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26
Q

Where can (R)-cadherin be found

A

Retina

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27
Q

What cells typically express endothelial (EV)-cadherin (Cad 5)?

A

vascular endothelial cells

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28
Q

What is key function of classical cadherins

A

They mediate calcium-dependent homotypic cell-cell adhesion

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29
Q

What role do classical cadherins play during embryogenesis

A

They mediate cell sorting

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30
Q

What structures do classical cadherins help form

A

They help in forming intercellular junctions such as adheren junctions, gap junctions, tight junction and desmosomes

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31
Q

How do classical cadherins contribute to cellular function

A

They assist in establishing cell polarity and can inhibit apoptosis while regulating growth factor receptors

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32
Q

How maney domains does E-Cadherin contain?

A

E-cadherin has five domains

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33
Q

Ehat is the role of the transmembrane domain in cadherins

A

The transmembrane domain anchors the cadherin to the cell membrane

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34
Q

Name the intercellular molecules that the intercellular domain of integrin binds to

A

Beta-catenin and p120 are intercellular molecules that link the intercellular domain of integrin

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35
Q

Explain the function of CAD-HAV domain

A

The CAD-HAV domain binds the two cadherins drom adjacent cells contributing to cell-cell adhesions

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36
Q

How do well-differentiated, poorly invasive adenomas differ from invasive carcinoma in terms of E-Cadherin expression

A

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

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37
Q

How can E-cadherin levels and stability of the E-cadherin-catenin complex be deregulated

A

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

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38
Q

What are the three classes of molecules present in the ECM

A

Consists of structural proteins (collagen, elastins),
protein-polysaccharide complexes (proteoglycans) and
adhesive glycoproteins (fibronctins, laminins)

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39
Q

How many alpha and beta subunits do integrins have, and what do they form

A

Integrins possess 24 alpha subunits and 9 beta subunits forming multiple non-covalently bound heterodimeric transmembrane receptors

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40
Q

What are the four main groups into which integrins are classified

A

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

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41
Q

How do RTK or chemokine receptirs affect integrin receptors

A

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

42
Q

How do integrins associate with RTKs to impact cellular functions

A

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

43
Q

How are RTKs involved in metastasis and cancer progression

A

RTKs can mediate EMT and contribut to different stages of metastasis

44
Q

What is unique about the insulin receptor family amond RTKs

A

They are expressed as dimers and do not require a ligand to bind for dimerization

45
Q

How does the FGF receptor relate to cancer treatments targeting the EGF receptors

A

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

46
Q

Why is the VEGF receptor important in cancer

A

It plays a crucial role in angiogenesis and lymphangiogenesis, essential processes in tumor growth and spread

47
Q

What is the role of TF snail 1 and Snail 2 (slug) in EMT

A

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

48
Q

How is NF-kB linked to EMT

A

NF-kB, an inflammatory mediator, upregulates Snail, contributing to the EMT process

49
Q

What signaling pathways regulate EMT

A

GSK-3B
TGF-beta
and SMAD pathways

50
Q

What does GSK-3beta do?

A

destabilized beta-catenin, SMAD, Notch1, and Snail1 ; inhibiting EMT

51
Q

What does TGF-beta do

A

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

52
Q

What is the significance of E-N Cadherin switching in cancers

A

E-N cadherin switching, a late event in many cancers, influences cellular activities by increasing detachment, motility, survival, and growth

53
Q

True or false: there a 20X increase in Snail 1 in patients with metastatic vs non metastatic HCC (liver cancer)

A

true

54
Q

What is observed in clinical specimens regarding cadherin expression in various malignancies

A

Clinical specimens exhibit the presence or inappropriate cadherins, including N-cadherin, acress different malignancies

55
Q

What happens when non-metastatic carcinoma cells (MCF-7) overexpress N-Cadherin

A

Overexpression of N-cadherin in non-metastatic carcinoma cells cause them to become metastatic

56
Q

How does silencing N-Cadherin affect pancreatic carcinoma cells

A

Silencing N-cadherin in pancreatic carcinoma cells lead to a non-onvasive and non-metastatic phenotype

57
Q

What are the outcomes of transgenic expression of N-cadherin in mammary carcinoma models

A

Transgenic expression of N-Cadherin does not induce tumorigenesis nor alter tumor onset in mammary carcinoma models

58
Q

What conclusion can be drawn regarding Cadherin switching from these findings

A

Cadherin switching is identified as a late event, not directly oncogenic, but pivotal in promoting invasion and metastasis

59
Q

What are the mechanisms involved in individual-cell migration

A

Individual-cell migration involves pseudopod protrusion for tration, recruitment of proteinases to degrade the matrix and actomyosin contraction for movement

60
Q

How does collective cell migration differ from individual-cell migration

A

Collective cell migration employs similar mechanisms as individual-cell migration but involved coordinated movement of groups of cells

61
Q

Describe the process of tumor cell invasion through tissues

A

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

62
Q

What are MMPs dependent on in terms of their enzymatic activity

A

MMPs are zinc- and calcium- dependent enzymes

63
Q

What role do MMPs play in normal physiological conditions

A

They are physiologic mediators of matrix degradation

64
Q

How is the expression of MMPs regulated in the body

A

MMP expression is tightly controlled in the body

65
Q

What characterizes the structure homology among MMPs

A

MMPs share a high degree of structural homology but significantly differ in substrate specificity

66
Q

How are MMPs classified based on their action

A

MMPs are classified as collagenases, gelatinases, stromelysins, MT-MMPs, and others

67
Q

What significant role do MMPs play in cancer progression

A

MMPs have a critical role in invasion and metastasis

68
Q

What are some inhibitors of MMPs

A

EDTA and o-phenanthroline are inhibitors of MMPs

69
Q

How many gene products of MMPs are there in humans, what unique feature does MMP9 possess

A

There are 23 gene productof of MMPs in human, with MMP9 pssessing a type V collagen-like domain

70
Q

How are MMPs regulated in the body

A

MMPs are tightly regulated by gene expression, activation, inhibition, proteolytic cascades, and feedback mechanisms

71
Q

What triggers the activation of MMPs from their inactive state

A

MMPs are inactive when secreted but become active upon cleavage of their pro-domain chemically or by displacement though another proteinase

72
Q

What impart do MMPs have on metastasis and angiogenesis?

A

MMPs contribute to reduced metastasis and angiogenesis

73
Q

What specific roles do MT-MMPs plau?

A

MT-MMPs directly degrade the extrecellular matric, activate pro-MMPs and de-shed from the membrane

74
Q

How is MMP4 involved in breast cancer progression

A

MMP4 in breast cancer, is involved in vessel dissociation and intravasation, thereby increasing metastasis

75
Q

What have the phenotypes of MMP-deficient mice confirmed regarding MMP’s role in cancer

A

Phenotypes of MMP deficient mice confirm MMP’s significant role in carcinogenesis, and metastasis

76
Q

What findings emerged from studies using MMP-2 knockout mice?

A

Studie using MMP2 KO mice showed suppression of experimentally induced pancreatic carcinogenesis, angiogenesis and delayed mammary gland differentiation, along with mild growth retardation

77
Q

What effects were observed in studies using MMP9 KO mice

A

MMP9 KO mice exhibited suppression of experimentally induced skin and pancreas carcinogenesis, as well as decreased experimental metastasis

78
Q

What outcomes were noted in studies involving MMP11 KO mice

A

MMP11 KO mice displayed suppression of experimentally induced mammary carcinogenesis, reduced tumor cell survival and growth

79
Q

How did MMP14 KO mice repond in studies

A

MMP14 KO mice showed reduced collagen turnover and defective angiogenesis

80
Q

What defines invadopodia and their role in cancer cell invasion

A

Invadipodia are actin-rich plasma membrane protrusions linked to extracellular matric degration, crucial for cancer cell invasion and metastasis

81
Q

What initiates the formation of invadopodia and what stabilizes them

A

Integrin binding intiates their formation, while MT1-MMP recruitment stabilizes invadipodia

82
Q

What indicators mark the presence of invadopodia

A

F-actin, MMP9, Cortactin and degraded gelatin serve as indicators of invadopodia

83
Q

What is ADAM and its role in cellular signaling

A

ADAM (a disintegrin and metalloproteinase) disrupts integrin signaling; ADAM10 degrades E-cadherin, while ADAM17 activated amphiregulin and TNF-alpha

84
Q

What is ADAMT and where is it predominantly found

A

ADAMT (a disintegrin and metalloproteinase with thrombospondin motids) is predominantly secreted

85
Q

What are exmaples of inhibitors of MMPs found in plasma

A

Alpha-2-macroglobulin,
Alpha-1-proteinase inhibitor
Alpha-1-chymotripsin
Alpha-2-antiplasmin

86
Q

What are TIMPs and hoe do they act on MMPs

A

Tissue inhibitors of metalloproteinases (TIMPs) are highly speciific inhibitors produced by tumor or host cells, binding to and inhibiting MMPs regionnaly

87
Q

What is the role of ECM collagen in angiogenesis

A

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)

88
Q

What is a common site of metastasis for prostate cancer

A

Metastasize in bone

89
Q

In what organ does uveal melanoma commonly metastasize

A

Uveal melanoma primarily metastasize to the liver

90
Q

What role do chemokines play in tumor cell movement

A

Chemokines guide tumor cells toward specific target organs by attracting cells expressing chemokines receptors

91
Q

Which chemokine is specific to lymph nodes

A

CCL20 is expressed in lymp nodes

92
Q

What happens when tumor cells reach the site of metastasis

A

Tumo cells attach to vascular endothelial layers, release proteins, degrade the ECM, and experience increased proliferation

93
Q

What is the outcome of enhanced cell motility in metastasis

A

Enhanced motility allows cells to traverse the matric and reach the target organ where they proliferate

94
Q

How do tumor cells interact with platelets and neutrophils in blood

A

Tumor cells form microthrombi with patelets and neutrophils offereing protection and acting as a source of growth factors

95
Q

What role do microthrombi play in metastasis

A

Microthrombi protect tumor cells and serve as source of growth factors like TGF-beta and PDGF

96
Q

Which cells are unique to the liver and interact with tumor cells during early liver metastasis

A

Hepatic stellate cells are unique to the liver and interact with tumor cells in the early stages of liver metastasis

97
Q

What interaction occur during the activation of fibrosis in the liver

A

Tumor cells undergo adhesion, diapedesis, and interact with hepatic stellate cells, leading to dibrosis activation and angiogenesis

98
Q

Which cell procede tumor ells to the lung, establishing a pre-metastatic niche

A

Bone marrow cells precede tumor cells and establish a pre-metastastix niche in the lung

99
Q

What role do exosomes play in the pre-metastatic niche

A

Exosomes from pancreatic cells induce a pre-metastatic niche in the liver before tumor cell arrival

100
Q

What happes when tumor cells enter a dormant state

A

Some tumor cells enter a dormant state, transitioning from mesenchymal to epithelial state

101
Q

What is crucial for establishing liver metastases

A

Re-expression of Type IV Collagen is crucial for establishing liver metastases

102
Q

Why is addressing metastasis challenging

A

Metastasis is a dynamic process requiring different targeted therapeutic approaches for different stages

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