There seems to be a never ending set of claims regarding
genes and gene expression as related to various cancers. In this writeup we
present our opinions regarding this matter when we examine a recent paper relating loss of expression of SIRT1 and the resulting
expansion of high grade PIN, HGPIN. This is gene suppression examined in mouse models. Now this
examination is of interest for a multiplicity of reasons.
First, HGPIN is often problematic. We have examined HGPIN
some five years ago and demonstrated that in many cases it leads to PCa but in
some anecdotally observed cases the HGPIN may actually disappear. The
disappearance of HGPIN in a 24 core biopsy after a similar one none months
prior is not readily explainable under the current murine models. Specifically
most murine models as well as clinical studies tend to indicate that HGPIN is
irreversible. However there are cases demonstrating the reverse.
Second, Sirt1 is not, in my opinion, an apparently generally accepted gene related to malignant
or metastatic behavior. It does have multiple control points but in general it
is more related to neurological controls rather than controls over
adenocarcinomas. In addition it connects to certain histone acetylation
mechanism and thus presents a possible epigenetic linkage via histone control
of expression.
In this analysis we use the recent paper by Di Sante et al
as a touchstone to examine Sirt1 and its behavior and again to use the Press
around the paper as a way to examine how the researchers either directly or
indirectly present their work and its implications. We all know that a great
deal has been derived from murine models. However, they are not human. Humans
live longer and face many more assaults on their cells than mice do. PCa for
the most part is a cancer of old age. It is a cancer which putatively is driven
by a multiplicity of cell assaults, resulting in genetic changes and changes in
gene expression. Also we may be facing strong epigenetic alterations via
methylations and acetylations. Which are these is the driving factor we really
do not know.
Thus this presentation serves two purposes:
First, in my opinion, it is just another gene thrown on the table to be
examined. The question that should and must be asked is; what is causal? Ultimately
we must also understand the temporal sequences that give rise to these
processes and the causal elements of those temporal sequences.
Second, in my opinion, it is another demonstration of how one should
cautiously approach reporting results, both to the Press as well as in the
literature itself. Again, as it seems with the publishing of any and all such “discoveries”
we find the Press become an outlet for what may truly be exaggerated statements
regarding the immediacy of use for such an observation. Thus there is the key
question as to what the responsibility is to the researchers regarding balanced
presentation of the results.
The recent paper Di Sante et al states
:
Prostatic intraepithelial neoplasia is a precursor to
prostate cancer. Herein, deletion of the NAD+-dependent histone deacetylase
Sirt1 induced histological features of prostatic intraepithelial neoplasia at 7
months of age; these features were associated with increased cell proliferation
and enhanced mitophagy.
In reality the statement is not definitive. We have observed
HGPIN actually disappearing and doing so for prolonged periods. The question
is; what makes HGPIN disappear. Also there is still a lack of total clarity as
to the genetic progression of PCa. One may still consider inflammation as a
major cause and possible mitigation of inflammation being a reason for the
reversal of HGPIN. However that also is conjecture. The problem here is the
definitive statement regarding HGPIN.
In human prostate cancer, lower Sirt1 expression in the
luminal epithelium was associated with poor prognosis. Genetic deletion of
Sirt1 increased mitochondrial superoxide dismutase 2 (Sod2) acetylation of
lysine residue 68, thereby enhancing reactive oxygen species (ROS) production
and reducing SOD2 activity.
The question on the expression of Sirt1 is; is this a cause
or an effect, or is it a concomitant from some related but no causal element?
The PARK2 gene, which has several features of a tumor
suppressor, encodes an E3 ubiquitin ligase that participates in removal of
damaged mitochondria via mitophagy. Increased ROS in Sirt1−/− cells enhanced
the recruitment of Park2 to the mitochondria, inducing mitophagy. Sirt1
restoration inhibited PARK2 translocation and ROS production requiring the
Sirt1 catalytic domain. Thus, the NAD+-dependent inhibition of SOD2 activity and
ROS by SIRT1 provides a gatekeeper function to reduce PARK2-mediated mitophagy
and aberrant cell survival.
Sirt1 seems to be a gene whose function, if expression is
reduced, could lead to malignant behavior. Now articles like this often get
significant Press coverage. In Medical express we have
:
Prostate cancer affects more than 23,000 men this year in
the USA however the individual genes that initiate prostate cancer formation
are poorly understood. Finding an enzyme that regulates this process could
provide excellent new prevention approaches for this common malignancy. Sirtuin
enzymes have been implicated in neurodegeneration, obesity, heart disease, and
cancer. Research published ...
show the loss of one of sirtuin (SIRT1) drives the formation of early prostate
cancer (prostatic intraepithelial neoplasia) in mouse models of the disease. "Using genetic deletion we found that SIRT1 normally
restrains prostatic intraepithelial neoplasia in animals. Therefore too little
SIRT1 may be involved in the cellular processes that starts human prostate
cancer," ... "As we had shown that gene therapy based re expression of
SIRT1 can block human prostate cancer tumor growth, and SIRT1 is an enzyme
which can be targeted, this may be an important new target for prostate cancer
prevention."
Upregulation of SIRT1 is one path and developing a
therapeutic for initiating that upregulation is also critical. However there
may be a multiplicity of other factors that would or could be required. The
mouse studies are clearly not definitive for humans. They are suggestive at
best.
The researchers ...created a mouse model
that lacked SIRT1 and noticed that these mice were more likely to develop an
early form of prostate cancer called prostatic intraepithelial neoplasia (PIN).
One of our ongoing concerns is the use of mouse models. We
know that they are useful for certain studies but problematic for others. In
addition a knockout mouse may have more complex genetic interactions that a
random human.
Other researchers had shown that SIRT1 can defend the
cell against damage from free radicals. ... took the work further
by showing that in this prostate cancer model, free radicals built up in cells
lacking SIRT1. They showed that normally, SIRT1 proteins help activate a
mitochondrial protein called SOD2, in turn activating those proteins to keep
free-radical levels in check. When SIRT1 level are diminished, SOD2 is no
longer effective at removing free radicals, allowing a dangerous build up in
the cells, and leading to PIN.
Now Pestell and his group are highly respected and they have
reported on Sirt1 effects before
.
"The next step," says first author ... "is to determine if this is also important in the development
of human prostate cancer."
Overall it is known that Sirt1 does works against inflammatory
tendencies. The last statement however is critical. It is clear that the
determination for human cells is still problematic. This seems to be one of the
major problems in murine models. The mouse prostate growth is not always the
same as human. Goldstein et al some five years ago did studies in mice
regarding the cell leading to HGPIN and thus PCa. Was it a basal cell or a
luminal cell? Carrying this over the humans was and is not definitive in any
manner.
Let us briefly examine HGPIN. HGPIN is an excessive growth
of cells in the glandular regions composed of an amalgam of basal and luminal
cells. It is an excess of growth within the confines of existing cells. It
often appears as a hyperplasia, but since the cells do not appear exactly as
they were in a normal region, they are considered as neoplasia. The luminal
space surrounded by the luminal cells tends to get crowded by these new cells
which tend to be confined to existing glandular locations. The growth we would
see in a Gleason 1 or 2 is generally not seen, namely the cells do not start to
proliferate outside of existing glands, or creating new glandular areas.
HGPIN is often observed in cases where there is a sudden
increase in PSA, generally above 6.0. However HGPIN can also be present in low
PSA cases, below 1.9 and it is often in these cases where it may regress.In a paper by Lefkowitz et al the authors note:
In a high proportion of men with high grade prostatic
intraepithelial neoplasia prostate cancer will develop in a 3-year interval.
Our findings support the concept that high grade prostatic intraepithelial
neoplasia is a precursor to prostate cancer and that repeat biopsy at a delayed
interval is recommended regardless of changes in PSA….
The question is; what caused the biopsy in the first place?
Generally it was due to a material increase in PSA. In the study the average
PSA was about 6.5, which is low and the average age was 65. We also know that
the prevalence of PCa in say the seventh decade of life if one were to biopsy
the entire prostate could be well above 50%.
It is difficult to determine precisely the natural
history of a single high grade prostatic intraepithelial neoplasia lesion since
it is not feasible to follow-up with precision the exact areas of abnormality
on repeat biopsy. Since the natural history of prostatic intraepithelial
neoplasia has not been elucidated, current recommendations for serial repeat
biopsy have not been validated by evidence based medicine, and several
investigators have reported results of follow-up biopsies. To our knowledge there have been no reports of follow-up
interval biopsy in a cohort of men with high grade prostatic intraepithelial
neoplasia independent of changes in PSA or digital rectal examination findings.
We provide insight into the natural history of high grade prostatic
intraepithelial neoplasia by performing an empiric follow-up interval biopsy 3
years after the initial diagnosis regardless of change in PSA or digital rectal
examination.
The paucity of studies regarding HGPIN follow up appears to
be the same as it was a decade ago when this paper was written.
A high proportion of men with high grade prostatic
intraepithelial neoplasia will have prostate cancer, independent of changes in
PSA, 3 years following initial diagnosis. Our study reaffirms the approach that
men with high grade prostatic intraepithelial neoplasia and no evidence of
coexisting cancer should be followed and re-biopsied to exclude prostate
cancer. Our longitudinal data in men with high grade prostatic intraepithelial
neoplasia strongly support the concept that it is a risk factor for the
development of prostate cancer, thereby further validating the lesion as a
target for chemopreventive and therapeutic agents. We recommend a 3-year follow-up
interval biopsy in men with high grade prostatic intraepithelial neoplasia,
regardless of change in serum PSA.
The conclusion is critical. Namely they recommend that a 3
year biopsy be done after a positive HGPIN determination. However what if after
a HGPIN determination a 9 month biopsy comes back normal, no HGPIN at all, then
should one go back again, independent of PSA? That is problematic. We have
argued that PSA has a normal growth pattern and like some many medical
observations if things continue on the same course, slow progression, then
perhaps that is a better alternative. However, it may also be prudent to
perform these biopsies, albeit being quite expensive and having some modicum of
morbidity. The question seems to be still unanswered.
We now will examine Sirt1 and the family of genes from which
it derives the Sirtuins. These genes have generally been examined in other
venues and not PCa. However they are well examined and we shall consider them
in some detail.
We begin with the work of Guatente has recently written an
extensive review paper on Sirtuins and especially Sirt1 in NEJM. It concludes
as follows:
Sir2 is one of a complex of proteins that mediate
transcriptional silencing at selected regions of the yeast genome. Mutations
that extend the replicative life span of yeast mother cells have been shown to
increase the silencing activity of Sir2 at the ribosomal DNA repeats. Although
the silencing of ribosomal DNA has turned out to be an idiosyncratic feature of
aging in yeast, the role of Sir2-related gene products (sirtuins) in aging
appears to be universal. Sir2 orthologues slow aging in the nematode
Caenorhabditis elegans, in the fruit fly Drosophila melanogaster, and in mice.
The sirtuins have been shown to have NAD-dependent protein deacetylase
activity, which is associated with the splitting of NAD during each
deacetylation cycle…
The studies to date have been on yeasts and fruit flies and
there have been some studies on humans. However the main focus on sirtuins is
their beneficial effects on the aging process, and one suspects as an
antioxidant and anti-inflammatory type of behavior.
Of the mammalian sirtuins, SIRT1, 2, 3, 4, 5, and 6 have
been shown to have this activity. Some SIRT family members (e.g., SIRT4 and
SIRT6) also have ADP-ribosyltransferase activity. In mammals, the Sir2
orthologue SIRT1 is primarily a nuclear protein in most cell types and has
evolved to deacetylate transcription factors and cofactors that govern many
central metabolic pathways. Targets of SIRT1 include transcriptional
proteins that are important in energy metabolism, such as nuclear receptors,
peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), and forkhead
box subgroup O (FOXO). SIRT1 also regulates components of the circadian
clock, such as BMAL1 and PER2, which underscores the interconnectedness of
protein acetylation, metabolism, circadian rhythm, and aging. SIRT1 is also
closely coupled to AMP-kinase activity in a mutually enforcing mechanism that
adjusts cellular physiology for conditions of energy limitation.
Sirt1 is the gene of focus yet Sirt2-6 also play roles, none
of which seem to have a role in PCa. The FOXO target is of considerable
interest
.
The earliest connection between SIRT1 and endothelial
cells was the finding that SIRT1 deacetylates and activates endothelial nitric
oxide synthase (eNOS). The activation of eNOS and repression of AT1 suggest
that SIRT1 activity ought to curb high blood pressure. SIRT1 also inhibits the
senescence of endothelial cells, and its salutary effect on these cells may
mitigate atherosclerosis. Interestingly, calorie restriction is known to
protect against atherosclerosis,46 and many of the physiological effects of
calorie restriction are blunted in eNOS−/−mice.21 These findings all indicate
that SIRT1 helps facilitate the favorable effect of calorie restriction on
cardiovascular function by its effects on eNOS, AT1, and perhaps other targets.
From Powell et al we have as more detailed discussion of the
functions of Sirt1:
The Sirtuin family of proteins (SIRT) encode a group of
evolutionarily conserved, NAD-dependent histone deacetylases, involved in many
biological pathways. SIRT1, the human homologue of the yeast Silent Information
Regulator 2 (Sir2) gene, de-acetylates histones,
p300, p53, and the androgen receptor. Autophagy is required for the degradation
of damaged organelles and long-lived proteins, as well as for the development
of glands such as the breast and prostate. Herein, homozygous deletion of the
Sirt1 gene in mice resulted in prostatic intraepithelial neoplasia (PIN)
associated with reduced autophagy. Genome-wide gene expression analysis of Sirt1/ prostates
demonstrated that endogenous Sirt1 repressed androgen responsive gene
expression and induced autophagy in the prostate. Sirt1 induction of autophagy
occurred at the level of autophagosome maturation and completion in cultured
prostate cancer cells. These studies provide novel evidence for a checkpoint
function of Sirt1 in the development of PIN and further highlight a role for
SIRT1 as a tumor suppressor in the prostate.
The autophagy cleans up the cells and brings them back to a
normal stasis. The recognition of Powell et al regarding the role of Sirt1 is
key. They continue:
The role of SIRT1 in regulating prostate gland formation and
androgen signaling in vivo was previously unknown. SIRT1is expressed in several
cell types in the prostate gland including basal cells, luminal cells, and
stromal cells. Given the evidence that SIRT1 functions as a tissue-specific
regulator of cellular growth and that SIRT1 inhibits tumor cell line growth in
nude mice, we sought to determine the role of endogenousSirt1 in regulating
prostate gland development. Genome-wide expression profiling of Sirt1/ mice
prostates and their littermate controls identified a molecular, genetic
signature regulated by endogenous Sirt1.
The above clearly shows the understanding of the function of
Sirt1. Note that the Powell work was in 2010 so that this understanding has
been available for a while.
This signature highlights the ability of Sirt1 to inhibit
androgen signaling and apoptosis in the prostate, while promoting autophagy.
The Sirt1/ prostates demonstrated epithelial hyperplasia and PIN suggesting that
Sirt1 promotes autophagy and inhibits prostate epithelial cell proliferation in
vivo.
The above demonstrates the ability of Sirt1 to control
androgen signalling. This also is a key factor in controlling prostate health.
Gene expression analysis further demonstrated that loss
of endogenous Sirt1 inhibited autophagy. At a higher level of resolution, our
studies demonstrated that SIRT1 antagonized DHT-mediated inhibition of
autophagy in the prostate. Autophagy allows for degradation of proteins and
organelles and is induced by nutrient withdrawal, rapamycin
(inhibition of mTOR signaling), and hormone signaling . Our findings are consistent with prior studies demonstrating that
SIRT1 induces autophagy by deacetylating ATG5, ATG7, and ATG8 and inhibits
AR signaling via deacetylation of the AR . Comparisons with previously
published studies identified an overlap of 12.45% between genes regulated by
endogenous Sirt1 and those targeted by androgens in the prostate gland and in
prostate cancer cells. These results are consistent with prior findings that
Sirt1 inhibits ligand-dependent AR signaling and gene expression in vitro
Again we come back to the role of autophagy. Perhaps the
buildup of protein segments may act as normal cell blockage, inhibiting normal expression
and control. The autophagy allows for a return to such normality. The emphasize
this issue as follows:
The role of autophagy in cancer was proposed over 20
years ago. Autophagy appears to be essential for tumor suppression as well as
for cell survival. Autophagy plays a prosurvival function for cancer cells
during nutrient deprivation or when apoptotic pathways are compromised, a
phenotype often accompanied by inflammation.
Again we see the putative role of inflammation. This appears
to be a significant factor in PCa and the suppression of genes which deal with
the remnants of inflammation seem to be a key benchmark in PCa progression.
They continue:
In contrast, upon disruption of tumor suppressors,
autophagy adopts a pro-death role with apoptotic pathways. In prostate, breast,
ovarian, and lung cancer, loss of Beclin1 or inhibition of Beclin1 by the BCL-2
family of proteins causes defective autophagy, increased DNA damage, metabolic
stress, and genomic instability. These
cancers also display neoplastic changes and increased cell proliferation,
unlike cells overexpressing Beclin1, which undergo apoptosis. Loss of PTEN,
p53, ATG4, ATG5, and MAP1LC31 (ATG8) are linked to tumorigenesis, whereas
upregulation of PI3K, AKT, BCL-2, and mTOR are associated with inhibition of
autophagy and the promotion of tumorigenesis. Prostate cancer onset and
progression are correlated strongly with aging and SIRT1 function governs aging
in multiple species. Further studies will be required to determine whether this
checkpoint function of Sirt1 in regard to prostate growth is linked to its role
in organismal aging.
From Shackelford et al we have additional insights including
pathway control issues as follows:
AMPK has recently been shown to increase sirtuin 1 (SIRT1)
activity by increasing cellular NAD+ levels, resulting in the regulation of
many downstream SIRT1 targets, including FOXO3 and peroxisome proliferator
activated receptor-γ co-activator 1 (PgC1; also known as PPARgC1A), both of
which have also been proposed to be direct substrates of AMPK46,76. As SIRT1 is
also implicated in tumorigenesis, this connection between AMPK and SIRT1 might
further explain how nutrients control cell growth. AMPK also suppresses
mTOR-dependent transcriptional regulators to inhibit cell growth and
tumorigenesis. Two mTORC1-regulated transcription factors involved in
cell growth are the sterol-regulatory element-binding protein 1 (SReBP1) and
hypoxiainducible factor 1a (HIF1α). SReBP1 is a sterolsensing transcription
factor that drives lipogenesis in many mammalian cell types. mTORC1 signalling
is required for nuclear accumulation of SReBP1 and the induction of SReBP1
target genes78, and this can be inhibited by rapamycin or AMPK agonists
From Hines et al we have an expression of Sirt1 in terms of overall
cell control:
The NAD + -dependent deacetylase SIRT1 is an
evolutionarily conserved metabolic sensor of the Sirtuin family that mediates
homeostatic responses to certain physiological stresses such as nutrient
restriction. Previous reports have implicated fluctuations in intracellular NAD
+ concentrations as the principal regulator of SIRT1 activity. However, here we
have identified a cAMP-induced phosphorylation of a highly conserved serine
(S434) located in the SIRT1 catalytic domain that rapidly enhanced intrinsic
deacetylase activity independently of changes in NAD + levels. Attenuation of SIRT1 expression or the use of a
nonphosphorylatable SIRT1 mutant pre- vented cAMP-mediated stimulation of fatty
acid oxidation and gene expression linked to this path- way. Overexpression of
SIRT1 in mice significantly potentiated the increases in fatty acid oxidation
and energy expenditure caused by either pharmacological b -adrenergic agonism
or cold exposure. These studies support a mechanism of Sirtuin enzymatic
control through the cAMP/PKA pathway with important implications for stress responses
and maintenance of energy homeostasis
From Dominy et al we have:
From an evolutionary perspective, the nutrient-dependent
control of protein acetylation through acetyltransferases and deacetylases is
highly conserved and is a major mechanism for coupling metabolic activity with
carbon/energy availability. The regulated acetylation of PGC-1a by GCN5 and
Sirt1 is an excellent example: PGC-1a acetylation by GCN5 is favored under
conditions of nutrient/energy abundance, whereas deacetylation by Sirt1 is
favored under conditions of nutrient dearth and high energy demand
Finally Brooks and Gu state:
SIRT1 is a multifaceted, NAD+-dependent protein
deacetylase that is involved in a wide variety of cellular processes from
cancer to ageing. The function of SIRT1 in cancer is complex: SIRT1 has been
shown to have oncogenic properties by down regulating p53 activity, but recent
studies indicate that SIRT1 acts as a tumour suppressor in a mutated p53
background, raising intriguing questions regarding its mechanism of action. Here we discuss the current understanding of how SIRT1
functions in light of recent discoveries and propose that the net outcome of
the seemingly opposite oncogenic and tumour-suppressive effects of SIRT1
depends on the status of p53.
They clearly indicate the tumor suppressor role of Sirt1.
p53 status is important but the observation above is truly intriguing if it is
sustained.We have examined miRNAs in previous papers and they may play
a key role here as well. The control of Sirt1 may be done via miRNAs. As
Pekarik et al note:
Importance of miRNAs is underscored by the fact that
nearly half of the genes coding miRNAs are located at fragile sites or at
regions with lost homozygozity. For example, a loss of p-arm of chromosome 1 is
a common finding in sporadic colon carcinomas. Among many genes associated with
DNA repair, checkpoint functions, tumour suppressors, etc. are also multiple
miRNAs. The most critical is miR-34a, directly regulated by tumour suppressor
gene p53 and classified now as tumour
suppressor itself. Ectopic miR-34a expression induces apoptosis and a cell
cycle arrest in G1 phase. Downstream targets of miR-34 are Bcl2, MYCN, NOTCH1,
Delta1, CDK4 and 6, Cyclin D1, Cyclin E2, c-Met, SIRT1, and E2F3, all the genes
involved in apoptosis or proliferation and cell growth control…
We have discussed miRNAs and especially mrR-34 as part of
PCa process. The control Sirt1 by miR-34 is a key observation It links back to
a cause. Thus one may surmise that this is a potential initiator and the miR-34
expression generated in some feedback manner with the inflammation which would
have been controlled by Sirt1.
We now first make several observations and then we conclude
with some possible recommendations.
1. What are the roles of miRNAs?
We have examined miRNAs extensively before. Yet they seem to
have an enduring role in reducing the activity of certain genes. The questions
here are; what activates the miRNAs, what are the targets for suppression, and
why?
2. What causes the suppression of Sirt1?
We have seen an argument for miRNA suppression of Sirt1.
However there may be multiple other arguments. Is it a consequence of an
already malignant process or is it a path towards such a development? Frankly
we do not seem to have clear answers. This becomes a significant factor when we
try to model PCa and its metastatic processes.
3. Is HGPIN the first step in loss of Sirt1 expression?
As Goldstein et al had noted regarding the cell of origin of
PCa and especially HGPIN, there is a well-defined genomic alterations leading
to this result but yet the details seem to be unknown.
4. Why does HGPIN at times seem reversible? Is it a temporal
anomaly?
The reversion seen at times in HGPIN is a significant factor
that leads one to ask; why and what is the process. Many conjecture can be made
ranging from elimination of a stem cell to reduction of inflammatory states.
The problem is that adequate clinical data seems to be missing from analyses.
5. What Genes are key and what Genes are there as a
Consequence? And why?
We have examined many dozens of purported genes related to
PCa. They continue to arise each time some researchers examine new cells. For
example in a study done contemporaneously to the one in this discussion we have
one by Thomsen et al regarding JUNB, a transcription factor
.
They conclude
:
Prostate cancer is a frequent cause of male death in the
Western world. Relatively few genetic alterations have been identified, likely
owing to disease heterogeneity. Here, we show that the transcription factor
JUNB/AP-1 limits prostate cancer progression. JUNB expression is increased in
low-grade prostate cancer compared with normal human prostate, but
downregulated in high-grade samples and further decreased in all metastatic
samples. To model the hypothesis that this downregulation is functionally significant,
we genetically inactivated Junb in the prostate epithelium of mice. When
combined with Pten (phosphatase and tensin homologue) loss, double-mutant mice
were prone to invasive cancer development. Importantly, invasive tumours also developed when Junb
and Pten were inactivated in a small cell population of the adult anterior
prostate by topical Cre recombinase delivery. The resulting tumours displayed
strong histological similarity with human prostate cancer. Loss of JunB
expression led to increased proliferation and decreased senescence, likely
owing to decreased p16Ink4a and p21CIP1 in epithelial cells. Furthermore, the
tumour stroma was altered with increased osteopontin and S100 calcium-binding
protein A8/9 expression, which correlated with poor prognoses in patients.
These data demonstrate that JUNB/AP-1 cooperates with PTEN signalling as
barriers to invasive prostate cancer, whose concomitant genetic or epigenetic
suppression induce malignant progression.
But is this gene, a transcription factor causal or
consequential? The same can be said about the gene Sirt1 as discussed herein.
The list of putative PCa related genes seems to grow by the day.
6. Why do researchers all too often make claims which are at
best a stretch?
To best understand this point, which we have made several
times, let us examine another Press release. As noted in Eureka
:
Prostate cancer affects more than 23,000 men this year in
the USA however the individual genes that initiate prostate cancer formation
are poorly understood. Finding an enzyme that regulates this process could
provide excellent new prevention approaches for this common malignancy. Sirtuin
enzymes have been implicated in neurodegeneration, obesity, heart disease, and
cancer. Research ... show the loss of one of sirtuin (SIRT1) drives the formation of
early prostate cancer (prostatic intraepithelial neoplasia) in mouse models of
the disease.
Let us examine the clarity of this statement in light of
what we have presented.
They are:
i) The individual genes driving prostate cancer. Do we
understand them? We do some, but we also have a plethora of dozens of others
whose increase or decrease is somewhat correlated with PCa.
ii) Developing prevention. One develops prevention if and
only if one understand the cause or causes and one can then mitigate the
processes which lead to those aberrant actions. Frankly at best we can say that
inflammation may be a problem but then what part of the complex inflammatory
process do we address?
iii) Yes we know Sirt1 and its system genes (proteins) act
in certain ways in a wide variety of ailments. But recognizing is presence to
cause to prevention is still a long and uncertain process.
Thus the opening statement is possibly in my opinion an exaggeration.
"Using genetic deletion we found that SIRT1 normally
restrains prostatic intraepithelial neoplasia in animals. Therefore too little
SIRT1 may be involved in the cellular processes that starts human prostate
cancer," .... "As we had shown that gene therapy based re expression of
SIRT1 can block human prostate cancer tumor growth, and SIRT1 is an enzyme
which can be targeted, this may be an important new target for prostate cancer
prevention."
It was not clear that they had shown a therapeutic that
allowed for the re-expression of Sirt1 in mice not less than in humans. The
process of Sirt1 suppression was not identified and thus suppressing the
suppression is uncertain. At least that is what one understands reading the
available literature.
The researchers ....created a mouse model
that lacked SIRT1 and noticed that these mice were more likely to develop an
early form of prostate cancer called prostatic intraepithelial neoplasia (PIN). Other researchers had shown that SIRT1 can defend the
cell against damage from free radicals. ... took the work further
by showing that in this prostate cancer model, free radicals built up in cells
lacking SIRT1. They showed that normally, SIRT1 proteins help activate a
mitochondrial protein called SOD2, in turn activating those proteins to keep
free-radical levels in check. When SIRT1 level are diminished, SOD2 is no
longer effective at removing free radicals, allowing a dangerous build up in
the cells, and leading to PIN.
SOD2 is supported by Sirt1 and thus we see the HGPIN build
up. One suggestion is to examine those patients who have HGPIN regression, to
see if it has been sustained and moreover what expressions were reactivated or suppressed.
Based upon the above we would make the following
recommendations.
1. HGPIN Regression study: We would recommend a detailed
HGPIN Regression Study. Simply records of multiple biopsies of HGPIN patients
should be considered and examination of those with regression within the next
biopsy period should be examined. Then retrospective examination of the patient
and their behavior should also be examined. This is a simple first step. It can
be accomplished by simple data gathering and no Trial structure is required.
2. HGPIN Regressed Genes Presence
One of the challenges in prostate biopsies is the ability to
return to the same location from which the original cells were obtained. Thus
even with a high density biopsy of say 24 cores we cannot be certain that we
have resampled the original dysplasia. his is even the case with ultrasound
guidance, yet it would seem possible to have recorded the location and to have
a sophisticated ultrasound system replace the new sample to close proximity to
the old. That way there could be a resampling of the same cells.
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