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CAN > Week 11 > Flashcards

Week 11 Flashcards

1
Q

What does tumour micro environment look like

A

Tumours are made up of malignant cells these comprise the majority of cell types that make up the cancer
Multiple non malignant cell types found in tumours- these cells have variable functions which are important in ensuring the survival growth metastatic spread and allowing for evasion of cancer from immune system
-cancer associated fibroblasts, pericytes, endothelial cells, myeloid cells, lymphocytes
Non cellular components of cancer microenvironment: constituents of ECM like collagens-structural integrity and act as signalling molecules

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2
Q

Co evolution

A

Stromal cells may co-evolve with the tumour ie stromagenesis occurs alongside tumorigenesis
Contributes to tumorigenesis

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3
Q

Many cancers associated with inflammation

A

Virchow postulated link between cancer and inflammation
Eg hepatitis->. Hepatocellular cancer
Helicobacter pylori gastritis-> gastric cancer
IBD-> colon cancer
In humans NSAIDs and COX-2 inhibitors reduce cancer risk
Mouse models: in a transgenic mouse system expressing the HPV16 early region genes, a lack of mast cells reduced the development of skin cancer

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4
Q

Hodgkin lymphoma

A

Malignant cells- Hodgkin and reed sternberg HRS
Surrounded by prominent non tumour components made up of lots of different cell types. Majority of the large mass in Hodgkin lymphoma is made up of non malignant cells of tumour microenvironment
Some are eosinophils
Surrounding T cells providing growth and survival signals to the HRS cells to enable them to survive
The HRS cells providing signals to T cells enable them to become active and proliferate symbiotic environments

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5
Q

The immune system can kill cancer cells

A

Tumour microenvironment is in general tumour promoting
The main types cells capable of killing cancer cells: cytotoxic T cells: recognise antigen and kill cells, natural killer cells: anti tumour effect
Tumours display local immunosuppression due to production of cytokines by tumour cell also cell capable of killing cancer are overwhelmed by other cells in microenvironment preventing them from killing them

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6
Q

Lymphocytes exit and entry

A

Some cancers entirely dependent on their microenvironment: Hodgkin lymphoma
Explanation recruitment in Hodgkin:
-involves 2 lipids- lysophosphatidic acid and sphingosine-1-phosphate
-lysophosphatidic acid is crucial for recruiting cells to tissue environment: HRS cells produce a lot
-the cells that are recruited can also leave
-the lipid pathway responsible for retention of cells is sphingosine-1-phosphate. As levels increase in cancer then receptors on surface of lymphocytes decline and cells won’t move out
Lysophosphatidic acid promotes lymphocyte entry:
-blood vessel formation
-tumour growth and invasion
-neuropathic pain
-lymphocyte homing
This explains why Hodgkin patients have lymphopenia- stuck in cancer tissue

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7
Q

Soluble factors

A

Soluble factors produced by tumour cells modify stromal cell function as well as recruitment
Lysophospatidic acids and sphingosine-1-phosphate are 2 soluble fatcors
Cancer cell produces variety soluble factors include migration, recruitment, retention of immune cells, pre-existing cells in tissue can be modified by soluble factors so their function is. Changed such as myofibroblasts, macrophages and fibroblasts
PDGF responsible for modification, differentiation fibroblasts, into myofibroblasts, recruitment and modification of macrophages and modification of myofibroblasts

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8
Q

Myofibroblasts

A

Altered form of fibroblasts
Hybrid properties of fibroblasts and smooth muscle cells
Produce collagen and other matrix proteins they can contract
Important for normal wound healing- important for contraction wounds
Found in breast- lactation
Found in excessive amounts in certain cancers- breast cancer

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9
Q

Cancer associated fibroblasts contribute to multiple pathways in cancer progression

A

By producing:
-collagen. Dense collagen difficult for immune cells get to tumour
-other soluble immunosuppressive agents TGF beta
-growth factors HGF
-proangiogenic factors VEGF
-MMPI (extracellular membrane degrading enzymes)

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10
Q

Evidence for involvement of CAF in tumour growth

A

Sub lethal irradiation of cancer associated fibroblasts followed by implantation with pancreatic cancer cells led to more aggressive tumours than implantation with normal fibroblasts (CAFs can promote tumour progression)
Ectopic expression of soluble factors eg HGF or TGF- beta by genetically modified fibroblasts induces breast cancer in normal breast epithelial cells (CAFs caused alterations in normal epithelia)

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11
Q

Cancer associated fibroblasts produce abnormal extracellular matrix

A

ECM produced by cancer associated fibroblasts if often dense and referred to as ‘desmoplastic’
The stroma can be growth promoting eg growth factors IGF1, HEGF can be tethered to the ECM
Pancreatic adenocarcinoma

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12
Q

Collagen can promote tumour cell growth

A

Collagen can promote cell growth HRS cells and protects them from chemo drugs
Discoidin domain receptor-1 DDR1 is an oncogenic tyrosine kinase that binds collagen
-binding of collagen induces conformational change which leads to an active receptor
Abnormal DDR1- mutation in receptors can lead to constitutively active receptor

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13
Q

Macrophages and cancer

A

Macrophages behave differently in different tissue environments
2 main groups of macrophages in cancer:
-M1: produce reactive oxygen species, pro inflammatory, provides defines against bacteria, they participate in Th1 - T cell mediated immunity. They have anti tumour activity
-M2: different cell surface receptors, produce different cytokines and are involved in tissue remodelling and angiogenesis, they have an immunosuppressive anti inflammatory response they are pro tumour
These two forms are interchangeable
M1- defence against bacteria, tumour suppression, immunostimualtion
M2- tissue repair and angiogenesis, tumour promotion , down regulation M1 and adaptive immunity

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14
Q

Molecular stratification

A

Tumour cell intrinsic: molecular features of tumour cells themselves
Tumour cell extrinsic: molecular features of tumour microenvironment

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15
Q

Immune therapy

A

Many cancers have cells present which are capable recognising and killing tumour cells but they are overwhelmed
If we can activate those small number tumour specific T cells we could provide a very effective therapy
This is now possible: we can give patients inhibitors to the immunosuppressive mechanisms (immune checkpoints) this unleashes the anti tumour immune response - effective in Hodgkins

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16
Q

Tumours are heterogenous (single cell RNA sequencing)

A
17
Q

Predictive biomarkers for checkpoint blockade therapies

A

Anti-PD1 mAB therapy: PD-L1 could be a positive predictive biomarker for treatment response
Dramatic durable clinical responses even on late stage metastatic cancers
Therapeutic benefit in many solid tumours
Mechanistically likely to rely on immune recognition of mutating peptide antigens on the tumour
PDL1 on tumours constantly being evaluated as on positive prediction biomarker for treatment response

18
Q

What is a chronic disease

A

NHS: a long term physical health condition (also known as a chronic condition) is a health problem that requires ongoing management over a period of years or decades and is one that cannot currently be cured but can be controlled with the use of medication and/or other therapies
US CDC: chronic diseases are defined broadly as condition that last 1 year or more and require ongoing medical attention or limit activities of daily living or both
US NCL: a disease or condition that usually lasts for 3 months or longer and may get worse over time. Chronic diseases tend to occur in older adults and can usually be controlled not cured

19
Q

Is cancer a chronic disease

A

For decades we have treated some early stage or low grade cancer which are not immediately life threatening but which need long term follow up or monitoring surveillance
For example non muscle invasive bladder cancer

20
Q

How have we increased cancer diagnosis and survival

A

Screening and early detection: patients diagnosed at earlier stages of disease such that survival beyond 5 years is very realistic
Widespread use of diagnostic imaging: asymptomatic cancers identified during investigations for other complaints “incidentalomas”
Better treatments: even incurable or late stage disease can be controlled to enable many patients to live for years after diagnosis

21
Q

New early detection tests eg GALEAS tm bladder

A

Capture of key mutation prone sections of DNA, ligation of unique molecular identifiers and targeted next generation sequencing

22
Q

Cancer survivorship care: essential components

A

Prevention of recurrent and new cancers and of other late effects
Surveillance for cancer spread, recurrence, or second cancers and assessment of medical and psychosocial late effects
Intervention for the consequences of cancer and its treatment
Coordination between specialists and primary care providers to ensure that all of the survivors health needs are met

23
Q

Common issues for cancer survivors

A

Pain
Fatigue
Fear of cancer recurrence
Uncertainty about future, work and finances
Some will be long term treatment effects (started during treatment) and some will be late effects (started months or years after treatment)

24
Q

Long term and late physical effects

A

Pain- chronic pain syndromes can be related to specific treatments new pain could suggest cancer recurrence or progression
Cardiac dysfunction- anthracyclines (doxorubicin, epirubicin) and radiotherapy to the chest ( especially >30Gy)
Metabolic syndrome- hormonal changes (drug, surgery). Resistance and aerobic exercise recommend
Lymphoedema- blockage, removal, scarring of the lymphatic system
Peripheral neuropathy: chemotherapy- induced (taxanes, platins etc) typically sensory
Immune related adverse events IrAEs- from immune checkpoint inhibition. Evidence still emerging regarding long term and late effects
Bone health- often as a result of hormonal changes (drugs, surgery) beware of metastasis

25
Q

Psychosocial issues

A

Anxiety and depression
Fear of cancer recurrence
Chemotherapy associated cognitive impairment- ‘chemobrain’ including problems with memory and concentration. To be distinguished from depression/fatigue/ sleep problems
Fatigue
Sleep problems- insomnia, sleepiness, sleep related breathing difficulties
Sex and intimacy
Return to work: 35% of cancer survivors are 40-64years and may want to return to work; becoming unemployed is 37% higher in cancer survivors
Financial toxicity- ‘out of pocket expenses’ even in universal health systems (eg NHS)

26
Q

The NCCN distress thermometer

A

Survey how much distress
Management

27
Q

For child and young adult survivors of cancer

A

Survivorship can span six decades
Organ systems that are developing during childhood and adolescence can be irreversibly affected by cancer treatment
Cure rates are high but many survivors face a long follow up period with numerous long term health risks
Common late effects include cardiovascular diseases, respiratory dysfunction, endocrine abnormalities, and subsequent malignant neoplasms

28
Q

Tumour microenvironment is formed as result of

A

Cell-ECM interactions
Cell-cell interactions
Communication mediated by soluble factors
Communication mediated by extracellular vesicles (ef exosomes)

29
Q

Role of lysophosphatidic acid LPA in the tumour microenvironment

A

Produced extracellularly
LPA formed from LPL- lysophospolipids but ATX (autotoxin)
LPA- affect cancer cell growth, tumorigenesis, survival, proliferation and invasion
Effects LPA tumor microenvironment:
-T cell activation, T cell infiltration, CAF generation fibrosis, glycolitic shift, angiogenesis

30
Q

Role of sphingosine-1 phosphate S1P in tumour microenvironment

A

Treg expansion migration and accumulation in cancer, suppresses host response to cancer and cytotoxic activating NK cells- immunosuppression of anti-cancer response, tumour progression
Produced inside cancer cells
Differentiate monocytes to M2 macrophages -> signalling pathway-> anti inflammatory cytokines IL-10, IL-4
Increase COX2-> PGE2 facilitate angiogenesis
S1P induces myofibroblast differentiation. MMPs and GF and ECM components -> invasion growth

31
Q

Immune microenvironment in cancer

A

Anti tumour cells: dendritic cells, cytotoxic T cells, natural killer cells
Tumour promoting immune cells: T regulatory, myeloid suppressive cells, neutrophils, tumor associated macrophages

CAN (11 decks)

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