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Tumour microenvironment
Both neoplastic epithelial (carcinoma) cells, and non-neoplastic stromal cell types populate a
tumour
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Heterotypic signalling
describes communication between dissimilar cell types
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Stromal
cells may also influence epithelial cell proliferation and survival in the tumour mass
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Stromal-epithelial interactions play a role in all stages of tumour progression
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The locations and large populations of stromal cells
within carcinomas indicate that the growth of epithelial components of these tumours is
accompanied by coordinated proliferation of stromal cells
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Neoplastic
cells within melanomas release ODG, which elicits IGF-2 production from nearby stromal
fibroblasts, IGF02 maintains the viability of melanoma cells
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Tumour cells, especially those present at the invasive front, can have an
immunosuppressive effect
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Many immune cells are present in the tumour microenvironment (TM), these can
be visualized via multiplexed (fluorescence) immunohistochemistry
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Collagen contributes to the tensile strength of the tissue
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Collagen accumulates- tumour ECM stiffness increases by the formation of covalent intraand inter- molecular cross-links- stimulates the invasive properties of the tumour cells
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Myeloid-derived suppressor cells (MDSCs)
MDSCs are a population of myeloid derived cells generated during a number of pathologic
conditions
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MDSCs can be classified into granulocytic
or polymorphonuclear MDSCs (PMN-MDSC) which represent a pathologic activation of

relatively immature neutrophils, monocytic MDSCs (M-MDSCs) which represent a pathologic
activation of monocytes, and early stage MDSC (E-MDSC) which represent cells with a
colony forming activity and other myeloid precursors
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In cancer, granulocyte-macrophage colony stimulating factor, granulocyte
colony stimulating factor, and macrophage colony stimulating factor, are overproduced and
favor the generation MDSCs
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These signals, in the form of growth factors and
inflammatory mediators, are relatively weak and of long duration
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This state of
activation is characterized as pathologic, and is associated with inhibition of adaptive
immunity and support of tumour progression
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The accumulation of MDSC depends on two groups of interconnected
signals
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The first group signals is driven by factors produced by tumours of the bone marrow stroma
in response to chronic infection and inflammation, and includes; GM-CSF, G-CSF, M-CSF,
S-SCF, VEGF, polyunsaturated fatty acids, transcription factors STAT3/5, IRF8, C/EBPbeta,
NOTCH, adenosine receptors A2b, NLRP3, retinoblastoma protein 1, and alarmins SIU A9
and A8
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The second group of signals is mediated by inflammatory cytokines and DAMP, including;
IFN-gamma, IL-1beta, IL-4, IL-6, IL-13, TNF and TLR ligand MMGB1
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M-MDSCs can be
identified due to expression of the surface markers CD11c and HLA class II
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Human PMN-MDSCs have a gene expression profile that distinguishes then
from neutrophils in cancer patients, and from healthy donors, including; eukaryotic
translation initiation factors 2 and 4 associated with ER stress, upregulation of mTOR
signalling, the MAPK pathway, CSF1, and the IFN-gamma regulated pathways
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The inhibition of FAD affects the immunosuppressive functions of
MDSC and enhances the efficacy of cancer immunotherapy
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ER stress also controls MDSC survival in tumours
and favor apoptosis through TNF-related apoptosis induced ligand receptor 2 and caspase 8
activation
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Studies show a positive
correlation of MDSC numbers in peripheral blood with cancer stage and tumour burden in
colorectal carcinoma, breast, bladder and thyroid cancer
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In e meta-analysis,
elevated numbers of MDSC in the circulation was found to be an independent indicator of
poor outcomes in patients with solid tumours
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In melanoma and hepatocellular carcinoma, PMN- and M- MDSC correlated with
poorer outcomes
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MDSC can predict responses to
cancer therapy
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PMN-MDSC numbers negatively correlated with chemotherapy response in
colorectal cancer
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The percentage of circulating M- and PMN-MDSC numbers
negatively correlated with clinical response to ipilimumab in patients with unresectable
melanoma
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Tumour associated macrophages (TAMs)
Important components of the tumour stroma include macrophages which are involved in
tumour rejection, promotion and metastasis
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TAMs promote tumour growth by facilitating angiogenesis,
immunosuppression and inflammation, and can also influence tumour relapse after
conventional anticancer therapies
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A small proportion of TAMs
arise from tissue resident macrophages and are maintained through in situ proliferation
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The differentiation of
inflammatory ly6c high monocytes into TAMS depends on RBPJ, the transcriptional regulator
of Notch signalling
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Inhibition of STAT3 caused by upregulation of CD45 phosphatase
activity is a key process that mediates the differentiation of MDSCs into TAMs
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macrophages can be
classified as classically activated (M1) or alternatively activated (M2)
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M1 macrophages secrete proinflammatory cytokines and effector molecules
including reactive nitrogen intermediates and express chemokines such as CXCL9/10
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The inappropriate release of these cytokines can result in
chronic inflammation and tissue damage
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M2a is stimulated in response to IL-4, IL_13, and fungal and helminth
infections
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M2b macrophages are stimulated by immune
complexes and bacterial LPS and exhibit upregulated expression of CD206 and the MER
receptor tyrosine kinase
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M2c macrophages are activated by IL-10
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M2d macrophages are stimulated by
TLR ligands and adenosine
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TAMs secrete
proinflammatory cytokines, TNF-alpha, IL-6, and IL-1 beta, in response to pathogens, eg
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cigarette smoke, creating a mutagenic

environment in the subepithelial stroma
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The resulting chronic
inflammation is linked to certain cancers, such as hepatocellular carcinoma, gastric cancer,
and lung cancer
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P13K gamma signalling in
TAMs inhibits NF-KB activation while stimulating C/EBP beta , thereby triggering a
transcriptional program that promotes immune suppression during inflammation and tumour
growth
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Macrophage
derived CXCL13 and CCL18 bind to their CXCCR%, CCR1 and CCR* receptors to promote
recruitment of eosinophils and naive T cells that suppress immune responses and promote
tissue remodelling
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Hypoxia us a
major driver if angiogenesis, and TAMs preferentially accumulate in poorly vascularised
regions during early tumour formation, increased macrophage tumour infiltration directly
correlates with blood vessel density in tumours proangiogenic macrophages are associated
with the M2 endotype and secrete TGF beta, VEGF, PDGF and fibrin
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A subset of M2 macrophages
express TIE2 on their cell surface and have a role in angiogenesis
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Macrophages are the
predominant cells at sites of basement membrane degradation during early tumorigenesis
and at the invasive front of tumours during malignant transformation
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Upregulation of CSF1 by tumor cells stimulates ,macrophage recruitment and
the production and ECF, which in turn promotes tumour cells migration
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Metastasis associated
macrophages (MAMs) are recruited by CCL2 and secret CCL3, which facilitates metastatic
seeding of breast cancer cells in the lung, for example
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The extent of macrophage infiltration serves as an important
diagnostic and prognostic biomarker in cancers
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M1
macrophages can be identified by CD40 and HLA-DR expression
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High macrophage density correlates with a favourable
outcome in colorectal cancer
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TAMs are critical determinants of prognostic responsiveness to
post surgery adjuvant chemotherapy due to reeducation of TAMs to restrain tumour
progression, thus the quantification of TAMS may also be used to stratify patients who are
more likely to respond post- surgically to chemotherapy
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A phase II study of caruman in
metastatic castration resistant prostate cancer patients showed that this antibody was well
tolerated, but the it either blocked the CCL2/CCR2 axis nor showed antitumor activity as a
single agent
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CCR2 antagonists
can block the mobilisation of CCR2+ monocytes from bone marrow to tumours in a mouse

model and pancreatic cancer and can lead to TAM depletion causing the inhibition of tumour
growth and distant metastasis
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CD40 activated
macrophages are indicative of the M1 phenotype
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CSF1/CSF1R blockers
target the activation of TAMs
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In vivo, CSF1R blockers reprogram macrophages to the M1 phenotype
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Favourable result of
several phase I, II, III clinical trials, full marketing approval from the european commission for
sue in ovarian cancer and soft tissue carcinoma
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Regulatory T cells
T regs are immunosuppressive cells that play roles in maintaining immune homeostasis and
self tolerance, T regs are divided into; thymic derived T regs (tTregs), autoreactive T cells
selected by a high avidity interaction with self antigens in the thymus; and peripheral T regs
(pTregs) induced from naive CD4 T cells by sub-optimal antigen presentation in the
periphery
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Tregs Exert
their suppressive activity via; suppressive cytokines (TGF-beta, IL-10, IL-35), immune
checkpoints and inhibitory receptors (CTLA-4, PD-1, LAG-3, TIM-3, ICOS, TIGIT, IDO),
direct cytotoxicity (perforin/granzyme mediated metabolic disruption of T effector cell activity
(IL-2 consumption), and induction of tolerogenic DCs, which promote T cell exhaustion and
expansion
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In cancers, Tregs
suppress antitumor immune responses and contribute to the development of an
immunosuppressive TIME, thus promoting immune evasion and cancer progression
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Treg
depletion followed by cancer antigen vaccination generated effective anti-tumour CD4+ and
CD8+ T cell responses in metastatic breast cancer patients
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Treg
infiltration and accumulation can correlate with a positive prognosis in certain malignancies,
including colorectal and gastric cancers
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Tregs are recruited into tumours in response to chemokines secreted by tumour cells and
innate immune cells, key chemokine-chemokine receptor combinations include
CCL17/22-CCR4, CCL5-CCR5, CCL28-CCR10, and CXCL9/10/11-CXCR3
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suppressive Tregs can be generated from
non-suppressive CD25- conventional T cells driven by tumour derived transforming growth
factor beta and adenosine
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S1P signalling is necessary for Treg accumulation within the TME, acting via the
JAK/STAT3 signaling pathway
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DCs and Tregs exhibit
bi-directional cross-talk, influencing the immune response both in physiological and
pathological settings
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Tregs influence DC maturation, by producing
TGF-beta and IL-10 and upregulating inhibitory B7-H3Y4 molecules on DCs, directing Dcs
towards a tolerogenic phenotype and improving their ability to activate Teff and CTLs
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Treg depletion by low-dose chemotherapy or CD25 targeted antibodies prior to adoptive cell
therapies, cancer vaccinations or other treatment modalities significantly enhances patient
survival and development of an effective antitumor immune response
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ICIs have seen successes in
clinical trials of non-small cell lung cancers and melanoma, inducing tumour regression and
remission free survival
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ICIs may also deplete or functionally impair Tregs
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As such, recent trials are testing
radiotherapy in combination with ICI or neoadjuvant chemotherapy to deplete Tregs
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Blockade of suppressive mechanism and soluble mediators, IL-10 and TGF-beta, may
impair Trig functions
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Extracellular vesicles
Extracellular vesicles (EV) are a heterogenous group of cell derived membranous structures
comprising exosomes (50-150nm), microvesicles (>100nm-1 micrometre), and large
oncosomes (>1 micrometre)
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EVs are present in biological fluids and
are involved in multiple physiological and pathological processes
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EVs are involved in cancer cell communication EVs shuttle reciprocal signals
and other molecules between transformed and stromal cells, including fibroblasts,
endothelial, and immune cells
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EVs promote anti cancer therapeutic
resistance throughout the targeted tumour
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EVs can form from the endomembrane system or through budding/blebbing from the
plasma membrane
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The subsequently generated early
endosomes (EE) fuse and mature to late endosomes (LE)
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MVBs are then destined for fusion with the plasma membrane, to

form exosomes
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EVs are released upon Rab dependent MVB-PM fusion
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Oncosomes can be artificially induced through
knockout of the cytoskeletal protein DIAPH3
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EVs can contain; lipids such as
sphingomyelin, phosphatidylcholine, phosphatidyl-ethanolamine; genetic material such as
mRNA, miRNA, rRNA, tRNA; proteins such as tetraspanin, receptors, adhesion proteins,
transporters and channels, vesicle trafficking related proteins, cytoskeletal proteins, and
cytosolic proteins
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CAFs are large spindle shaped cells
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fibroblasts activation protein alpha (FAP alpha) is
selectively expressed by activated CAFs in various types if human epithelial cancer
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IGFBP7 expressing CAFs have been demonstrated to promote
colon cancer
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Microarray
gene analysis identified expressed genes in CAFs compared to normal fibroblast cell lines
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The activated phenotype of fibroblasts in the tumour mass are induced by genetic and
epigenetic changes that are self regulated and regulated by cancer cells, and by cytokines
secreted by cancer cells and other stroma cells, such as TGF-beta, EGF, PDGF, FGF2, and
CXCL
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miRNAs have a regulatory role in the transformation of NFs to CAFs
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CAFs produce autocrine and paracrine cytokines
that promote tumour growth, including EGF, hepatocyte growth factor (HGF), CAF secreted
proteins secreted frizzled related protein 1 and IGF like family member 1 and 2
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MSC0 derived CAFs are recruited to the stroma of
the dysplastic stomach and express IL-6, WNt 5 alpha, and bone morphogenetic protein 3,
all of which promote tumour growth through DNA hypomethylation
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CAFs
produce vascular endothelial growth factor (VEGF), a cytokine involved in angiogenesis
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PDGF/PDGFR signalling is an
important regulatory pathway involved in angiogenesis
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Cancer cells induce the
secretion of IL-6 from fibroblasts, thus inducing tumour angiogenesis
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CAFs induce
intraepithelial neoplasia in prostate epithelial cells
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CAFs in the stroma of triple negative breast cancer select for bone metastatic
cells
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Increased Wnt activity results in increased
migration and invasion of endometrial cancer cells
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CAFs induce

resistance of cancer cells to otherapy
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Cancer cells induce
the production of MMPs by fibroblasts, which results in degradation of the ECM and
enhances the invasiveness of cancer cells
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Cancer cells
produce PDGF, which induces fibroblast proliferation and the expression of IGF-½
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these signalling pathways cat in positive feedback loops
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Cancer
cells may alter the adjacent stroma ro create a microenvironment that permits and supports
tumor growth
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CAFs are not susceptible to apoptosis CAFs are elongated
mesenchymal cells positive for alpha smooth muscle actin (alpha-SMA), fibroblast activation
protein (FAP), Thy-1 desmin and the SIO4 positive fibroblasts that surround ducts, glandular
structures and aggregates of neoplastic cholangiocytes
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