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CANC380 > Module 03 - Tumour microenvironment > Flashcards

Module 03 - Tumour microenvironment Flashcards

1
Q

What is the Tumour Microenvironment?

A

All the cellular and extracellular components within a tumour, as well as tissues in its adjacent vicinity

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2
Q

What drives communications amongst the various cell types in the TME?

A

Network cytokines, chemokines, growth factors, inflammatory molecules and matrix remodeling enzymes

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3
Q

What can be targeted in the TME as a therapeutic strategy

A

common features of the TME shared by different tumours

Monitoring changes in TME composition could help to identify specific targets for therapy

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4
Q

What are the components of the TME?

A

Malignant cells, malignant cells in necrotic or hypoxic areas, Immune cells (NK and NKT cells, macrophage, T lymphocyte, B Lymphocyte, dendritic cells) lymphatics and vascular cells, fibroblasts and pericytes

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5
Q

What is angiogenesis?

A

process of formation of new blood vessels from pre-existing ones

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6
Q

How does a tumour increase its blood supply?

A

angiogenesis

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7
Q

What is lymphangiogenesis?

A

process of formation of new lymph vessels

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8
Q

What provides additional routes for metastatic spread of tumour cells?

A

Newly formed lymphatic vessels

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9
Q

Why do tumours undergo angiogenesis

A

they reach a size that cant be supported by current vasculature and thus needs more blood supply to continue its growth

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10
Q

How do tumours stimulate angiogenesis ?

A

Excrete proteins like Vascular Endothelial Growth Factor (VEGF) (7 types) + its receptors (3 types)
Can cause proliferation through the activation of kinase

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11
Q

What is the benefit of having both angiogenic inducers and inhibitors?

A

Allows for more precision in controlling the growth of blood vessels

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12
Q

What physiological factors stimulate angiogenesis

A

Low nutrient levels
ischaemia
trigger release of angiogenic inducers

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13
Q

What are some angiogenic inducers?

A

Vascular Endothelial Growth Factor (VEGF)
basic Fibroblast Growth Factor (bFGF)
Angiopoietins

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14
Q

What are some angiogenic inhibitors?

A

Thrombospondin-1 (TSP-1)
Angiostatin
Soluble fms-like tyrosine kinase (sFlt-1)

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15
Q

What are the functions of the pericytes in the TME?

A

1- presence and communication with endothelial cells promote vessel stability and permeability control
2- regulating the expression of endothelial cell-to-cell adhesion molecules
3- lack of pericyte coverage in blood vessels in the TME is at least partially responsible for their convoluted and leaky phenotype
4- low pericyte cover is indicative of poor prognosis and increased likelihood of metastasis

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16
Q

Describe the phenotype of TME blood vessels

A

Aberrantly branched

Leakier phenotype when compared to angiogenesis

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17
Q

How does the aberrantly branch and leaky phenotypic blood vessel create a selective pressure?

A

This phenotype disrupt blood flow, oxygenation and delivery of nutrients and drugs

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18
Q

Why is tumour angiogenesis indicative of a worsening prognosis?

A

Angiogenesis is required for further growth and delivery of nutrients and oxygen. indicative that the tumour is growing

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19
Q

What are 3 reasons why tumour blood vessels are abnormal?

A

1- higher concentration of VEGF
2- Expression of different VEGF isoforms
3- inconsistent VEGF concentration gradients

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20
Q

Why do higher concentration cause abnormal blood vessel?

A

they lead to leaky and branched vessels

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21
Q

Why does the expression of different VEGF isoforms cause abnormal blood vessel?

A

They have different binding capacities to endothelial cells and the ECM. They have widespread effects on capillary branching

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22
Q

Why does inconsisten VEGF concentration gradients cause abnormal blood vessels?

A

Consistent concentration is a key factor in normal blood vessel development

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23
Q

What were the benefits and drawbacks of angiogenesis for a tumour as identified in the article? (Angiogenesis in Cancer)

A

Benefits (2)
- Increased expression of VEGF has been associated with aggressive cancer, indicating angiogenesis plays a positive role in tumour growth
- because of their abnormal structure, new blood vessel also help tumours evade intravenous drugs such as those used in chemo
Drawback (1)
- Leaky blood vessels can result in excessive interstitial pressure on a tumour which can compromise its survival

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24
Q

What is hypoxia?

A

oxygen levels below those normally found in a tissue

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25
Q

What are most solid tumours characterized by?

A

hypoxia

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26
Q

What are the main reason why cells in solid tumours become hypoxic?

A
  • many cell layers = natural oxygen gradient forms with layers closest to the blood supply having greater abundance of oxygen. leaves cell on the inner layers subject to hypoxia
  • Cells in a tumour are metabolically active due to continuous signals to divide, thus reducing )2 levels in that tumour
  • Destruction of blood vessels or development of aberrant, leaky blood vessels that do not adequately deliver oxygen may exacerbate hypoxia
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27
Q

What are some vasculature defects that cause hypoxia?

A

Arteriovenous shunts
breaks in the vessel wall
temporary occlusions
blind ends

28
Q

Describe the blood flow in abnormal tumour vasculature

A

Often obstructed, sluggish

29
Q

What is the major pathway by which hypoxia affects the TME?

A

HIF-1, made up of an alpha and beta subunit, is the major transcription factor that mediates cellular adaptations to hypoxia

    • HIF-1 associated with poor prognoses and may result in activation of genes involved in cancerous phenotypes
      ex:
  • increased expression of VEGF leading to angiogenesis
  • decreased expression of E-cadherin promoting tumour cell migration
  • increased expression of PD-L1 which binds to PD-1 on T cells and decrease their function
30
Q

How does hypoxia affect TME? (2)

A

Tumour cell populations adapt to hypoxia acquiring certain survival traits
ex: hypoxia select cells that have mutations that inactivate TP53 (tumour suppressor gene) and are therefore resistant to apoptosis
- hypoxia also induces the expression of genes in tumour cells that increase the likelihood of their survival in the adverse hypoxic microenvironment; glucose transport and metabolism, angiogenesis, invasion and metastasis, and escape from immune destruction
–expression of these genes is mostly mediated by transcription factors called hypoxia-inducible factors (HIFs) there are 2 (HIF 1-3)
HIF-1 is the most well-studied

31
Q

Describe the structure of HIF-1

A

Heterodimer consisting of HIF-1alpha and HIF-1beta subunits

    • HIF-1alpha levels are controlled by tissue oxygen concentration. Levels increase in hypoxia because of decreased degradation of HIF-1alpha by the cell
  • HIF-1beta is constitutively expressed
32
Q

What is the role of HIF-1 in tumourigenesis?

A

Increasing the expression of VEGF leading to angiogenesis
Decreasing expression of E-cadherin, promoting EMT and tumour cell migration and invasion
Increasing the expression of genes involved in tumour cell immune evasion

33
Q

What is the mechanism of HIF-1alpha in normoxic environments?

A

Degradation of HIF-1alpha requires the von Hippel-Lindau tumour suppressor protein (pVHL). pVHL is the recognition component of E3 ubiquitin-protein ligase complex involved in the degradation of intracellular proteins: it is essential for maintaining a healthy proteasome in a cell

34
Q

What happens in cell lacking wild type pVHL?

A

They are unable to degrade HIF-1alpha and, as a result, express hypoxia-inducible genes, even under well-oxygenated conditions

35
Q

What is von Hippel-Lindau (VHL) syndrome?

A

Inactivation of both pVHL alleles leads to VHL syndrome, a hereditary condition that affects 1 in 35,000 people.
People with VHL syndrome have a high risk of:
blood vessel tumours or the retina and CNS, renal clear cell carcinomas pheochromocytomas, and other tumours

36
Q

what is the mechanism of pVHL-mediated O2-dependent regulation of HIF-1alpha under normoxic conditions?

A

1- pVHL binds to a region of the HIF-1alpha protein called the oxygen-dependent degradation domain (ODD) which requires hydroxylation of proline residues 302 and 564 in HIF-1alpha, carried out by HIF prolyl hydroxylases (HPH) 1-3 – this may be facilitated by acetylation of lysine (K) 532
2- Binding of pVHL to HIF-1alpha eventually directs the ubiquitination and degration of HIF-1alpha, by hydroxylating apasragine 803 in the C-terminal transactivation domain (TAD-C)This only happens in the presence of oxygen

37
Q

What is the mechanism of action of HIF-1alpha under hypoxic conditions?

A

The enzymes that degrade HIF-1alphas are inhibited in hypoxic conditions.
HIF-1alpha is translocated tothe nucleus, where it will form a heterodimeric complex with HIF-1beta. This heterodimer than transactivates hypoxia inducible genes such as VEGF and uPAR

38
Q

Describe the contribution of Tcells to the TME

A

comprise 10% of all cells in tumour tissues
both pro and anti-tumour phenotypes
Types of T cells present in the tumour vary depending on stage and type of cancer

39
Q

What kind of T cells are present in the TME? (5)

A
  • CD8+ memory T cells
  • CD4+ Th1 cells
  • CD4+ Th2 cells
  • Th17
  • Regulatory T cells
40
Q

What is the role of CD8+ memory T cells in the TME

A

Able to directly kill cancer cells once activated which is done in the lymph nodes when the tumour antigen is presented by antigen presented cells
associated with good prognoses

41
Q

What is the role of CD4+ Th1 cells in the TME?

A

Mediate the immune response against cancer, and are commonly referred to as Type 1 helper T cells
Required for cytokine-mediated activation of cytotoxic Tcells
can also eliminated cancer in absence of CD8+ Tcells
High CD4:CD8 T cells ratios are associated with good prognoses in lung and liver cancer

42
Q

What is the role of CD4+ Th2 cells in the TME?

A

CD4+ Type 2 helper T cells have a role in immunity against parasites usually
Exert anti-tumour immunity through IL-5 release which activates various tumourcidal cells
These have been found in more aggressive or advanced stage cancers

43
Q

What is the role of Th17 cells in the TME?

A

Th17 cells are helper T cells that promote inflammation and contribute to autoimmunity (thought to be important in maintaining barrier immunity at mucosal surfaces)
Higher levels of Th17 cells are found in tumours than in normal tissue - suggests that they are induced in and/or recruited to TME
Do no express high levels of PD-1, suggesting that they don’t contribute to immune suppression in TME

44
Q

What is the role of regulatory T cells in the TME?

A

CD4+ helper T cells subset, has a suppressive role in immunity
Tregs mediate peripheral tolerance by suppressing self-reactive T cells
Higher proportion of Tregs has been found in tumours as compared to peripheral blood in ovarian and lung cancer
T-reg mediated immunosuppression has been implicated in tumour immune-evasion mechanisms. It is a major obstacle in immunotherapy success

45
Q

What is the contribution of B cells to the TME?

A

Most commonly found in the lymph nodes close to the TME

- In some cancers, infiltration of B cells are associated with good prognoses

46
Q

Which type of cells is most commonly found in the lymph nodes close to the TME?

A

B cells

47
Q

What is the role of regulatory B cells in the TME?

A

Subpopulation of B cells involved in immune system regulation and suppression of immune response
- promote metastasis of lung cancer
- inhibit tumour-specific immune responses in some skin cancers
- associated with poor prognoses in mouse research models
Bregs appear to affect other immune cells in surrounding lymphoid tissue and modulate myeloid cell activity rather than infiltrate the TME themselves

48
Q

What is the contribution of NK cells and NK T cells to the TME?

A

cytotoxic cells of innate immunity that recognize and destroy tumour and virally-infected cells
- associated with good prognoses

49
Q

What is the role of NK T cells in the TME?

A

destroy tumour cells
can infiltrate tumour stroma bu not generally in contact with tumour cells
May not be able to exert tumour-killing function in the TME - studies identified anergic phenotype induced by malignant cell-derivde TGF-beta

50
Q

What are the 4 myeloid cells that contribute to the TME?

A

Tumour-associated macrophages
Myeloid-derived suppressor cells
Dendritic cells
Tumour-associated neutrophils

51
Q

What is the role of Tumour-associated macrophages in the TME?

A

Macrophages found in proximity to tumour cells that have 2 distinct phenotypes; M1 or M2

  • M1 cells suppress cancer progression
  • M2 cells are plentiful in hypoxic or necrotic areas of many cancers, contribute to angiogenesis, aid in malignant cell migration, invasion and metastasis
52
Q

Which type of Tumour-associated macrophage is considered “pro-tumour”?

A

M2

53
Q

Which type of Tumour-associated macrophage is considered “anti-tumour”?

A

M1

54
Q

What is the role of Myeloid-derived suppressor cells in the TME?

A

Heterogeneous population of cells in the immune system that increase in number in the presence of cancer and inflammation

  • inhibitory immune cells; they produce cytokine, IL-10, which inhibits cytotoxic Tcells
  • they induce development of Tregs and conversion of macrophages to TAM-like phenotype (M2)
55
Q

What types of cells are “pro-cancer”?

A 
Tregs
Bregs
M2 TAMs
Myeloid-derived suppressor cells 
Tumour-associated neutrophils
56
Q

What is the role of dendritic cells in the TME ?

A

Antigen processing and presentation (professional APC)

Thought to be defective in the TME and are also impaired by a hypoxic and inflammatory environment

57
Q

What is the role of Tumour-associated neutrophils in the TME?

A

controversial Contribution to tumour growth and metastasis
Can eliminate and disseminate cancer cells directly or indirectly through TGF-beta inhibition
Promote tumour growth in mouse cancer models
Anti-tumour function following immunological or cytokine activation

58
Q

What is the tumour stroma?

A

Composed of connective tissue, proteins, blood/lymph vessels and immune and inflammatory cells. It is dynamic and can change throughout the progression of the tumour and promote tumour growth invasion and metastasis.

59
Q

What is the role of Cancer-associated fibroblasts in the TME?

A

Abundant in many TMEs, can be derived from various precursors; epithelial, smooth muscle, mesenchymal stem cells. Increased density at the invasive front of a tumour

  • They secrete growth factors such as VEGF, chemokines, cytokines, ECM remodelling enzymes
  • Can restrict access of anti-cancer drugs by arranging themselves in structures, fibrovascular cores, that can branch and surround malignant cells
  • Induce angiogenesis
  • inhibit cytotoxic Tcells
60
Q

What is the role of the ECM in the TME

A
  • Contains growth factors that can influence tumour proliferation
  • TAMS, cancer-associated fibroblast and malignant cells release MMPs which allow for remodelling of ECM
  • Cleavage of ECM components by proteinases plays a role in the evolution and spread of cancers
61
Q

What is the role of adipocytes in the TME?

A
  • Aid the recruitment of malignant cells through secretion of adipocyte-derived adipokines and growth factors
  • Promote growth of malignant cells by providing fatty acids as fuel for growth
62
Q

What are some current therapies that target the TME?

A
  • immune checkpoint therapy
  • anti-angiogenesis
  • reprogramming myeloid cells
  • targeting the ECM to increase delivery of drugs to tumour
63
Q

Describe the interactions within the TME

A

All components interact and influence each other. Tumours have the potential to evolved on a much faster scale because of the synergistic nature of the TME factors. Due to this interconnectivity, eliminating only one factors (eg: hypoxia) does no necessarily impart a disadvantage to the tumour cells
This is one reason why the TME is such a potent selective pressure on cancer evolution

64
Q

What are the limitations of anti-angiogenesis therapy ? (5)

A
  • Decreased chemo perfusion (reducing blood flow to a tumour also reduces drug delivery to tumour cells)
  • Intrinsic resistance (some cell populations have resistance to this therapy before exposure - they can stimulate angiogenesis without VEGF or high survival in hypoxic environments)
  • Increased aggressiveness (increased selection for hypoxic cells increases aggressiveness of tumours)
  • Stem cell selection (results in higher numbers of tumour initiating stem cells to the tumour)
  • Acquired resistance (therapy act as selective pressure that gives an advantage to cells that can survive without VEGF as an angiogenic inducer)
65
Q

What is the basic interaction between hypoxia and angiogenesis?

A

cells in hypoxic tissue secretes angiogenic factors to stimulate growth of blood vessels

CANC380 (6 decks)

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