Understanding the potential mechanisms of action of dietary prostate carcinogens
File(s)
Author(s)
Graham, Oliver William
Type
Thesis
Abstract
Prostate cancer is the most commonly diagnosed cancer in males in the UK, and
while the precise aetiology of prostate cancer remains unknown, risk factors such as age
and lifestyle have been identified. Consumption of a ‘western’ diet rich in well-done red meat
has been implicated in the development of prostate cancer, due to the appreciable amounts
of carcinogenic material found in these foods. Two common dietary carcinogens are
benzo[a]pyrene (B[a]P) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), both of
which have been identified as possible prostate mutagens. Another possible risk factor for
prostate cancer is inflammation (a common condition in the prostate), specifically interleukin-
6 (IL-6) which is found elevated in the serum of prostate cancer patients. The underlying
mechanisms behind the influence of dietary carcinogens and inflammation on the
development of prostate cancer remain elusive, with limited knowledge about how
inflammation may alter the modes of action of dietary carcinogens in the prostate. I
hypothesised that IL-6 may alter the activation of B[a]P and PhIP, resulting in phenotypic
alterations to prostate cells that are associated with cancer development. Using an in vitro,
cell culture based model, the current project reported findings that both B[a]P and PhIP
induce alterations in prostate cell migration while demonstrating genotoxic potential.
Moreover, mixtures of B[a]P and PhIP induced significantly more genetic damage than either
chemical in isolation, suggesting that interplay during simultaneous exposure in vivo may
result in higher levels of DNA damage in the prostate. Further, PhIP-induced genotoxicity
appeared to be a result of cytochrome P450-mediated production of reactive oxygen
species. Finally, my data indicate that IL-6 increases B[a]P-mediated genetic damage,
suggesting that activation of B[a]P in prostate cells may be altered by inflammatory cytokines
such as IL-6, but more work is needed in order to verify this interaction. These novel findings
must be explored in greater depth in order to fully understand how these factors interact in
the prostate.
while the precise aetiology of prostate cancer remains unknown, risk factors such as age
and lifestyle have been identified. Consumption of a ‘western’ diet rich in well-done red meat
has been implicated in the development of prostate cancer, due to the appreciable amounts
of carcinogenic material found in these foods. Two common dietary carcinogens are
benzo[a]pyrene (B[a]P) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), both of
which have been identified as possible prostate mutagens. Another possible risk factor for
prostate cancer is inflammation (a common condition in the prostate), specifically interleukin-
6 (IL-6) which is found elevated in the serum of prostate cancer patients. The underlying
mechanisms behind the influence of dietary carcinogens and inflammation on the
development of prostate cancer remain elusive, with limited knowledge about how
inflammation may alter the modes of action of dietary carcinogens in the prostate. I
hypothesised that IL-6 may alter the activation of B[a]P and PhIP, resulting in phenotypic
alterations to prostate cells that are associated with cancer development. Using an in vitro,
cell culture based model, the current project reported findings that both B[a]P and PhIP
induce alterations in prostate cell migration while demonstrating genotoxic potential.
Moreover, mixtures of B[a]P and PhIP induced significantly more genetic damage than either
chemical in isolation, suggesting that interplay during simultaneous exposure in vivo may
result in higher levels of DNA damage in the prostate. Further, PhIP-induced genotoxicity
appeared to be a result of cytochrome P450-mediated production of reactive oxygen
species. Finally, my data indicate that IL-6 increases B[a]P-mediated genetic damage,
suggesting that activation of B[a]P in prostate cells may be altered by inflammatory cytokines
such as IL-6, but more work is needed in order to verify this interaction. These novel findings
must be explored in greater depth in order to fully understand how these factors interact in
the prostate.
Version
Open Access
Date Issued
2017-06
Date Awarded
2017-11
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Gooderham, Professor Nigel J
Sponsor
Imperial College London
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)