the tumour microenvironment and inducing or accessing vasculature

what cells make up the tumour microenvironment

• stromal cells

• immune cells

• vascular cells

what do cancer cells secrete lots of

VEGF because they require blood vessels for growth

what do cancer stem cells possess similar properties to

tissue stem cells

what are tissue stem cells are characterised by

• self renewal

• control on stem cell numbers

• ability to divide and differentiate to generate all functional elements of that particular tissue

what can cancer stems cells form that normal stem cells cant

can form tumours when transplanted in animals

what can cancer stem cells arise from

can arise from normal stem cells, progenitor cells or more differentiated cells (asymmetrical division) through multiple mutations of genes

what are cancer stem cells thought to have compared to normal cell stem cells

thought to have no control on their cell number: infinite proliferative capacity

what do cancer stem cells constitute

constitute a small number number of cells in the tumour and are thought to be responsible for the growth of other new tumour cells

what can cancer stem cells express

specific markers

what can cancer stem cells undergo

undergo EMT: invasion and metastasis

what do cancer stem cells have

enhanced resistance to chemotherapy drugs

why doesn’t chemotherapy doesn’t always work

chemotherapy can shrink cancer cells in the primary tumour but might not shrink cancer stem cells

what specific markers do cancer stem cells express that you can target

• CD133

• CD44

• CD24

what enzyme do cancer stem cells have that you can target

aldehyde dehydrogenase-ALDH

what transcription factor do cancer stem cells have that you can target

OCT4

what drug efflux pumps do cancer stem cells have that you can target

MDR1

what else should we consider in the tumour microenvironment

the oxygen concentration

what is hypoxia

low O2 levels

what is normoxia

normal O2 levels

what 2 things exist in the tumour microenvironment

• hypoxia

• normoxia

what type of tissue are cancerous tumours

heterogenous tissues with a dynamic microenvironment

what do cancerous tumours exhibit

an oxygen gradient with outer regions of normoxia tissue alongside experiencing hypoxia

normoxic cancer cells

• near blood vessels

• low HIF-1 alpha expression

• more susceptible to chemotherapy and radiation therapy

hypoxic cancer cells

• increased genetic instability

• poor immune response

• influence extracellular matrix remodelling/stiffness

• HIF-1 alpha expression results in altered angiogenesis

• less susceptibility to chemotherapy and radiation therapy

what does pimonidazole bind to

thiol-containing proteins specifically in hypoxic cells

why is necrosis a bad form of cell death as opposed to apoptosis

necrosis releases reactive oxygen species (ROS) which can cause damage to DNA therefore increasing DNA mutations

what can a lack of oxygen and ROS cause

necrosis

what causes necrosis

lack of oxygen delivery and impaired waste removal

what does necrosis result in

spilling of cellular contents causing inflammation and injuring to nearby cells

what does necrosis evoke

an inflammatory response

what do cancer cells need in order to grow

oxygen, nutrients and the ability to evacuate metabolic waste and CO2

how do cancer cells achieve growth

promoting the formation of new blood vessels- NEOANGIOGENESIS

what is necessary for tumour growth and metastasis

the angiogenic switch

what is the angiogenic switch

where the tumour goes from being dormant to secreting angiogenic factors which stimulate angiogenesis and resulting in neovascularisation

what is neovascularisation

• makes rapid tumour growth possible by supplying oxygen and nutrients and removing water

• facilitates metals

how is angiogenesis induced

1. tumours release proangiogenic factors- HIF1 alpha- hypoxia oncogenes

2. endothelial cells secrete MMP, digest the extracellular matrix, proliferate and growth toward the tumour

3. endothelial cells form new aberrant blood vessels that support tumour growth and dissemination

what creates a disorganised vascular network

the imbalance of pro- and anti-angiogenic signalling within different parts of tumours

compare normal and tumour vasculature

• normal blood vessels- organised and regular branching order (vascular heirarchy)

• tumour vasculature- disorganisation and lack of the conventional hierarchy of blood vessels

what do vascular abnormalities in the tumour result in

results in heterogeneity of tumour blood flow, which interferes with the homogenous distribution of a drug within the tumour

what does angiogenesis support

tumour growth and metastasis