Tumour Microenvironment (TME) Flashcards
what constitutes a tumour?
cancer cells and the tumour microenvironment
- immune cells
- stromal cells
crosstalk between cancer and stroma can support tumour growth
what are organs comprised of?
Parenchyma
stroma
what is parenchyma?
Parenchyma comprises the tissues that confer function
- tissue of organ that functions
- e.g. kidney parenchyma is epithelial
- e.g. spleen: parenchyma is connective tissue
- e.g. heart: parenchyma is muscle tissue (cardiac muscle cells)
what is the stroma?
Stroma supports the parenchyma:
- Without stroma, parenchyma cannot function - no organ can function without the mechanical and nutrient support of the stroma
Without stroma, tumour cannot grow
what is an example of a parenchyma and its stroma?
In the skin:
- Parenchyma – squamous epithelia
- Stroma: Dermis, fibrous connective tissue
the epithelial cells are tightly connected
the connective tissue is much looser
the blood vessels in the skin connective tissue (not the epithelia)
Both needed for function
how is the stroma involved in cancer?
Stroma is non-malignant cells that support the malignant parenchymal cells
- stroma is essential for tumour growth
tumour cells have the same needs as normal tissues
how are tumour cells complex ecosystems?
Multiple non-malignant cell types are found within
- Cancer-associated fibroblasts associated with cancer cells
- ECM
- Endothelial cells – blood vessels
- Myeloid and lymphocyte cells
where does cancer originate?
sustained proliferation
in a milieu rich in inflammatory cells, growth factors, DNA damaging agents
potentiates/promotes neoplasia
- originates at sites of chronic, persistent inflammation
- may be due to autoimmune inflammation e.g. inflammatory bowel disease, or due to infectious agents
what are examples of inflammation inducing cancer?
Barret’s oesophagus leads to chronic reflux of stomach acid into oesophagus
- This induces inflammation and metaplasia in oesophagus
– DNA damage and malignancy – oesophageal cancer
Hep B causes chronic inflammation in liver – increases risk of liver cancer
how can anti-inflammatory drugs reduce cancer risk?
Aspirin is anti-inflammatory and can decrease risk of CRC by dampening inflammation
- decreases the risk of metastasis
and decreases incidence after a few years
do certain cancers metastasise to certain tissues?
yes:
e.g. CRC tends to metastasise to liver
e.g. Ovarian cancer metastasise to peritoneal cavity
e.g. breast cancer preferentially metastasises to lungs and bone marrow
why is it strange that cancers metastasise in certain tissues?
Venous shunts allow large numbers of ovarian cancer cells to circulate yet metastasis outside of the peritoneal cavity is still rare
- cancers are constantly in circulation, but are specific in where they extravasate
- Transformed cells can’t grow anywhere
why do certain cancers preferentially metastasise to certain tissues?
2 theories:
- seed and soil theory
- alternative theory - due to anatomy of vascular and lymphatic drainage
both mechanisms/theories are likely important and true
what is the seed and soil hypothesis?
Proposes certain cancers metastasise to particular organs because metastasis is the result of favourable interactions between tumour cells (‘seed’) and the organ microenvironment (‘soil’)
- Secreted factors from primary tumour may influence the soil to be a preferable environment
what is the alternative theory of cancer metastasis?
Alternative theory – organ preference is due to anatomy of vascular and lymphatic drainage from site of primary tumour (e.g. lung is common site for metastasis)
- Hepatic portal vein takes blood into liver to be processed
- Tumour in colorectal tissue enters blood supply and reaches liver – why liver is one of the first metastatic tissues
what is an example of primary tumours altering the environment of the ‘soil’?
primary tumours can induce VEGFR-1 on distal lung cells, triggering MMP9 expression, making the lung more receptive to metastases
what are the key stages of wound healing?
- hemostasis
- humoural inflammation (vascular permeabilisation)
- cellular inflammation (immune cells infiltrate – neutrophils and macrophages)
- angiogenesis (formation of new blood vessels)
- generation of mature connective stroma
why does the body provide tumours with the stroma that is essential for tumour growth?
Tumours disguise themselves as wounds and call upon the host to heal them:
- Tumours continuously secrete factors that cause persistent angiogenesis and stroma formation
- Body provides support for tumour as it acts like a wound
- wound healing is usually self-limiting, but cancer is uncontrolled, so ‘wound’ never heals, and body continues to support
what tumour growth limited by?
Hypoxia
- oxygen only diffuses a distance of 0.2mm, so newly formed tumour hits hypoxia in the centre early on - pH and oxygen tension drops within the growing tumour
what are the two possible results of hypoxia in tumours?
- Can’t grow due to lack of blood supply and therefore lack of oxygen
OR
- cancer can change stroma to form new blood vessels for oxygen delivery to grow beyond fixed size – angiogenic switch
- Switch enables growth from small tumour to large solid tumour – this is supported by immune cells
how functional are the blood vessels that are produced in tumour angiogenesis?
New blood vessels are altered:
- Areas of hypoxia
- Areas of low blood supply
- Areas of necrosis due to lack of oxygen
Angiogenesis for cancer isn’t perfect – there are dead ends - not optimal
what kind of metabolism do tumours undergo?
low oxygen favours anaerobic respiration
- Warburg effect
- less efficient ATP production but increased production of biosynthesis factors for cell growth
- growth/survival advantage
- but anaerobic metabolism is less efficient, so more glucose is required to provide energy
what pH is in a TME?
Anaerobic metabolism forms lactic acid:
- there is build-up of lactic acid due to poor vascularisation, so waste products are not removed
- TME therefore has lower pH – favours tumour growth, unfavourable for immune cell function
TME also uses up lots of glucose – Warburg effect
why is interstitial fluid pressure higher in tumours?
Malformed blood vessels are leaky:
- IFP is similar to atmospheric pressure in normal tissues
- IFP is highly increased in solid tumours
- Caused by vascular abnormalities e.g.
high endothelial vessel permeability (promoted by VEGF) - vessels become leaky which reduces lymphatic function
- High IFP has important consequences reducing drug concentrations in tumours
why does high IFP reduce drug concentrations in tumours? How can this be overcome?
Difficult for therapy – drugs can’t access tissues as the vessels are malformed
- Drugs that target VEGF alone to stop angiogenesis in tumours are not effective
- When VEGFi given in combination with chemotherapy, there are better effects – VEGFi can restore blood vessels to improve chemotherapy access to tumour
what is the extracellular matrix (ECM)?
Within tissues, cells are surrounded by a network of proteins and proteoglycans termed ‘the extracellular matrix’.
- ECM serves as a basis for cell anchorage
- Collagen, the most abundant structural protein in the human body, is a major ECM component
