Lung cancer
cancer…
…and smoking…
g
Dr P
P. Keene
Department of Haematology and
M l
Molecular
l M
Medicine
di i
Objectives
• Explain the role of tumour initiators and
promotors
• Relate the known aetiological agents of lung
cancer to the initiator and promotor roles
• Describe the tumour microenvironment with
respect to inflammation
• Explain why tobacco smoking has both initiator
and promotor properties
• Discuss treatment of NSCLC in the molecular
era.
era
Aetiological agents in lung
cancer
• Smoking
S ki
But also:
•
•
•
•
Radon
Asbestosis
Any lung scarring such as old TB
Other
In general, there is cell death
and tissue injury
Occupational causes of lung cancer:
Number of attributable lung cancer registrations in 2004 for men
and women by carcinogen or occupational circumstance. (Britain)
Tumour initiators and promotors
• Initiators – cause mutations in DNA
• Promotors – factors leading to the
proliferation of initiated cells.
What roles do the traditional
aetiological factors in lung cancer
play?
• Initiators
• Promotors
P
t
• Both
Inflammation is now recognised
as a critical component for
tumour progression
It appears
pp
to be p
playing
y g a role as a
tumour promotor, although some
aspects of inflammation act as an
i iti t as well.
initiator
ll
Hanahan and Weinberg, 2011:
Hallmarks of Cancer:
The Next Generation
Tumour-promoting inflammation is
regarded
d d as an
essential “enabling characteristic”
in tumour formation
Background:
The Tumour Microenvironment
The microenvironment
surrounding cancer cells:
• Cells – other cancer cells as well as many
different non
non-cancerous
cancerous cells
• Extracellular matrix
• Soluble factors e.g.
g g
growth factors,,
chemokines, proteases…
Non-cancer cells – components
of all tumours
• All the cells that make up blood and lymph
p
y
etc.
vessels – endothelial cells,, pericytes
• Cancer-associated
C
i t d fib
fibroblasts
bl t
• Inflammatory cells – innate and adaptive macrophages ne
macrophages,
neutrophils,
trophils different
classes of lymphocytes
Cancer associated fibroblasts
Cancer-associated
Carcinoma cells
Fibrous tissue
Fibroblasts
“Scirrhous” carcinoma of the breast
Tumour fibrosis
Dense, white fibrotic cancer in a breast
Cancer associated fibroblasts
Cancer-associated
• “N
“Normal”
l” fibroblasts
fib bl t
• “Myofibroblasts” – contain actin. They secrete
many enzymes which remodel the
microenvironment e.g. matrix metalloproteinases,
as well as the collagen and other constituents of
the ECM. They are responsible for contraction of
wounds
d
Their importance has been demonstrated in
transplantation
p
experiments
p
Inflammatory cells as part of the
microenvironment
Morphologically this has been recognised for
centuries – Virchow,, 1863
The importance of these cells is now
appreciated but the exact mechanisms of
interaction between them and tumour are
only beginning to be understood.
Inflammatory
y cells
These occur in varying proportions in almost
allll cancers
Cancer‐
promoting effects
ff
Cancer‐
inhibiting effects
ff
Macrophages
Macrophages
p g
Inflammatory cells in cancer
Arrow: cancer cells
Arrowhead: lymphocytes
Arrowhead: lymphocytes
The Cancer-Inflammation
Relationship
• Inflammatory cells foster proliferation,
survival and migration of the cancer cells
• Cancer cells use inflammatory signaling
molecules
l
l and
d receptors
t
ffor migration,
i ti
invasion and metastasis
I early
In
l tumour
t
growth
th the
th tumour
t
cells
ll are
dependent on the inflammatory cells in the
microenvironment.
In late tumour g
growth many
yp
proinflammatory factors come under control of
tthe
e tumour
tu ou ce
cells
s tthemselves
e se es
e.g. COX-2 is produced by stromal cells in
early tumours,
tumours but by cancer cells in later
tumours.
Chemokines are central
central…
• Tumour cells appear to secrete
chemokines themselves or induce their
secretion by stromal cells, thus recruiting
inflammatory cells
• Some tumour cells use chemokines in
autocrine control off their own growth – this
has been shown in NSCLC – as well as
those produced by inflammatory cells
Back to smoking…
smoking
Smoking
S
ki appears tto be
b such
h a powerful
f l cause off
lung cancer as it contains both initiators and
promotors.
promotors
Smoking is a cause of INFLAMMATION as well as
containing carcinogens
The cancer risk
Th
i k reduces
d
in
i smokers
k
who
h quit
it b
butt it
does not return to normal - because of the
reduction in inflammation?
Inflammation as a carcinogen
The microbicidal mechanisms of neutrophils
p g involve the g
generation
and macrophages
of reactive oxidant species
ROS are capable of directly causing DNA
damage
Smoking
related
damage
in the lung
is not
confined
to the
tumour…
tumour
2
The future of treatment in non
small cell lung cancer:
Molecular pathology
gefitinib/
erlotinib
cetuximab
trastuzamab
crizotinib
2