Introduction
There has been a significant amount of confusion as to the
role of Vitamin D in either preventing or in controlling prostate cancer, PCa. The
results are often conflicting and have lacked details on why this may be the
case. In some cases it is seen as beneficial and in others it is actually seen
as having a deleterious effect. Just what the answer is may very well still be
uncertain. We focus here on a recent paper by Lambert et al.
We begin with a recent paper by Boland et al state the authors
summarize their clinical trial which demonstrates a negative correlation
between Vitamin D levels and the incidence of PCa. Specifically they state[1]:
Vitamin D insufficiency is associated with many
disorders, leading to calls for widespread supplementation. Some investigators
suggest that more clinical trials to test the effect of vitamin D on disorders
are needed. We did a trial sequential meta-analysis of existing randomized
controlled trials of vitamin D supplements, with or without calcium, to
investigate the possible effect of future trials on current knowledge.
We estimated the effects of vitamin D supplementation on
myocardial infarction or ischemic heart disease, stroke or cerebrovascular
disease, cancer, total fracture, hip fracture, and mortality in trial
sequential analyses using a risk reduction threshold of 5% for mortality and
15% for other endpoints. The effect estimate for vitamin D supplementation with
or without calcium for myocardial infarction or ischemic heart disease (nine
trials, 48 647 patients), stroke or cerebrovascular disease (eight trials 46
431 patients), cancer (seven trials, 48 167 patients), and total
fracture (22 trials, 76 497 patients) lay within the futility boundary,
indicating that vitamin D supplementation does not alter the relative risk
of any of these endpoints by 15% or more.
Vitamin D supplementation alone did not reduce hip
fracture by 15% or more (12 trials, 27 834 patients). Vitamin D co-administered
with calcium reduced hip fracture in institutionalized individuals (two trials,
3853 patients) but did not alter the relative risk of hip fracture by 15% or
more in community-dwelling individuals (seven trials, 46 237 patients). There
is uncertainty as to whether vitamin D with or without calcium reduces the risk
of death (38 trials, 81 173). Our findings suggest that vitamin D
supplementation with or without calcium does not reduce skeletal or
non-skeletal outcomes in unselected community-dwelling individuals by more than
15%. Future trials with similar designs are unlikely to alter these
conclusions.
Thus the above makes a clear assertion that the use of
excess Vitamin D does not alter end points in cancer cases.
Even more so, the work by Wong et al states:
Lower levels of vitamin D may reduce prostate cancer risk
in older men. By contrast, levels of vitamin D did not predict incidence of
colorectal or lung cancers. Further studies are needed to determine whether a
causal relationship exists between vitamin D and prostate cancer in ageing
men…. As illustrated …, every 10 nmol/l decrease in 25(OH)D concentration was
associated with a 4% reduction in prostate cancer incidence, after adjustment
for age, education, living circumstance, smoking status, physical activity,
CCI, BMI, creatinine, seasonality and previous diagnosis of cancer (other than
prostate) (SHR 0.96, 95% CI 0.92–1.00). Similarly, every halving of 25(OH)D
concentration was associated with a 21% reduction in incident prostate cancer
after adjustment for other risk factors.
In this study in Australia they clearly note that there is a
strong indication that lower Vitamin D blood levels yield lower PCa incidence.
However the authors (Wong et al) also note the conflicting results on those
with existing PCa. They write:
Whilst there is lack of conclusive evidence on the benefit
of vitamin D supplementation in the development of prostate cancer, previous
studies on the effect of pre-existing prostate cancer have so far produced
ambiguous results. A research team in the United States explored the influence
of vitamin D3 supplementation at 4000 IU daily for one year on the outcome of
early stage, low-risk prostate cancer ... More than half of the study subjects
remained stable or improved with supplementation, compared to a fifth of the
control group who did not receive supplementation (p= 0.025).
Conversely,
vitamin D3 supplementation did not benefit 40% of the subjects in this
open-label clinical trial. Another study involves the randomization of 37
patients with histologically proven adenocarcinoma of the prostate who had selected
prostatectomy as primary therapy. Calcitriol was administered to the treatment
group at 0.5 mg/kg per week for a 4-week period prior to surgery. When
prostatectomy specimens were processed and analyzed, VDR expression was
significantly reduced in samples from calcitriol treated patients (p = 0.004)
but there was no statistically significant difference in the fraction of cells
expressing the specific molecules involved with cell-cycle regulation and
proliferation
Thus with evidence of reduction with lower Vitamin D and
conflicting results with existing PCa patients it is useful to have some
baseline model of what Vitamin D does and why it may be effective.
In a NEJM paper by Hollick, the author states regarding cancers:
In a study of men with prostate cancer, the disease
developed 3 to 5 years later in the men who worked outdoors than in those who
worked indoors. … Children and young adults who are exposed to the most
sunlight have a 40% reduced risk of non-Hodgkin’s lymphoma and a reduced risk
of death from malignant melanoma once it develops, as compared with those who
have the least exposure to sunlight.
The conundrum here
is that since the kidneys tightly regulate the production of 1,25-dihydroxyvitamin
D, serum levels do not rise in response to increased exposure to sunlight or
increased intake of vitamin D.1-3 Furthermore, in a vitamin D– insufficient
state, 1,25-dihydroxyvitamin D levels are often normal or even elevated. The
likely explanation is that colon, prostate, breast, and other tissues express
25-hydroxyvitamin D-1α- hydroxylase and produce 1,25-dihydroxyvitamin D locally
to control genes that help to prevent cancer by keeping cellular proliferation
and differentiation in check. It has been suggested that if a cell becomes
malignant, 1,25-dihydroxyvitamin D can induce apoptosis and prevent
angiogenesis, thereby reducing the potential for the malignant cell to survive.
Once 1,25-dihydroxyvitamin D completes these tasks, it
initiates its own destruction by stimulating the CYP24 gene to produce the
inactive calcitroic acid. This guarantees that 1,25-dihydroxyvitamin D does not
enter the circulation to influence calcium metabolism. This is a plausible
explanation for why increased sun exposure and higher circulating levels of
25-hydroxyvitamin D are associated with a decreased risk of deadly cancers.
The issue with the above set of observations is that they
lack causative linkages which can be carried through in the cellular analysis.
GDF-15 and PCa
It is always useful to have a clear understanding of what
effect a molecule like Vitamin D has on specific pathways and particularly
regarding cellular control.
As Lambert et al have noted[2]:
Accumulating evidence suggests that chronic prostatic
inflammation may lead to prostate cancer development. Growth differentiation
factor-15 (GDF-15) is highly expressed in the prostate and has been associated
with inflammation and tumorigenesis. To examine the relationship between GDF-15
and prostatic inflammation, GDF-15 expression was measured by
immunohistochemical (IHC) staining in human prostatectomy specimens containing
inflammation. The relationship between GDF-15 and specific inflammatory cells
was determined using non-biased computer image analysis. To provide insight
into a potential suppressive role for GDF-15 in inflammation, activation of
inflammatory mediator nuclear factor of kappa B (NFκB) was measured in PC3
cells.
GDF-15 expression in luminal epithelial cells was
decreased with increasing inflammation severity, suggesting an inverse
association between GDF-15 and inflammation. Quantification of IHC staining by
image analysis for GDF-15 and inflammatory cell markers revealed an inverse
correlation between GDF-15 and CD3+, CD4+, CD8+, CD68+, and inos+ leukocytes.
GDF-15 suppressed NFκB activity in luciferase reporter assays. Expression of
the NFκB target, interleukin 8 (IL-8), was downregulated by GDF-15. The inverse
relationship between GDF-15 and inflammation demonstrates a novel expression
pattern for GDF-15 in the human prostate and suppression of NFκB activity may
shed light on a potential mechanism for this inverse correlation.
Note from the above:
1. GDF-15 suppressed NFκB
2. GDF-15 downregulates IL-8
3. GDF-15 concentration is inversely related to inflammation
and also shown below:
4. Vitamin D upregulates GDF-15
We summarize this below:
From Newswise we have the following report[3]:
A University of Colorado Cancer Center study recently
published in the journal Prostate offers compelling evidence that inflammation
may be the link between Vitamin D and prostate cancer. Specifically, the study
shows that the gene GDF-15, known to be upregulated by Vitamin D, is notably
absent in samples of human prostate cancer driven by inflammation.
“When you take Vitamin D and put it on prostate cancer
cells, it inhibits their growth. But it hasn’t been proven as an anti-cancer
agent. We wanted to understand what genes Vitamin D is turning on or off in
prostate cancer to offer new targets,” says James R. Lambert, PhD, investigator
at the CU Cancer Center and associate research professor in the CU School of
Medicine Department of Pathology.
Since demonstrating that Vitamin D upregulates the
expression of GDF-15, Lambert and colleagues, including Scott Lucia, MD,
wondered if this gene might be a mechanism through which Vitamin D works in
prostate cancer. Initially it seemed as if the answer was no.
“We thought there might be high levels of GDF-15 in
normal tissue and low levels in prostate cancer, but we found that in a large
cohort of human prostate tissue samples, expression of GDF-15 did not track
with either normal or cancerous prostate tissue,” Lambert says.
But then the team noticed an interesting pattern:
GDF-15 was uniformly low in samples of prostate tissue that contained
inflammation.
This observation is an interesting nexus. It is well known
that inflammation is a driver of PCa. It is seen increased in patients with
Type 2 Diabetes and obesity, two conditions with co-incident inflammatory
responses. The authors continue:
“Inflammation is thought to drive many cancers including
prostate, gastric and colon. Therefore, GDF-15 may be a good thing in keeping
prostate tissue healthy – it suppresses inflammation, which is a bad actor
potentially driving prostate cancer,” Lambert says.
The study used a sophisticated computer algorithm to
analyze immunohistochemical (IHC) data, a task that in previous studies had
been done somewhat subjectively by pathologists. With this new technique,
Lambert, Lucia and colleagues were able to quantify the expression of the
GDF-15 protein and inflammatory cells by IHC staining on slides taken from
these human prostate samples.
Additionally encouraging is that the gene GDF-15 was
shown to suppress inflammation by inhibiting another target, NFkB. This target,
NFkB, has been the focus of many previous studies in which it has been shown to
promote inflammation and contribute to tumor formation and growth; however,
researchers have previously been unable to drug NFkB to decrease its
tumor-promoting behavior.
As we shall further show, this may be a bit contradictory to
other evidence. As we had speculated before, increases in GDF-15 reduced NF-κB,
and thus reduced inflammatory factors. They then argue that it is the
inflammation and not the excess NF-κB that is the problem. However one must ask
what the cause of the inflammation is. They conclude:
“There’s been a lot of work on inhibiting NFkB,” says
Lambert. “Now from this starting point of Vitamin D in prostate cancer, we’ve
come a long way toward understanding how we might use GDF-15 to target NFkB,
which may have implications in cancer types far beyond prostate.”
Now from a second report, Prostate Cancer News, they state[4]:
“GDF-15 may be a good thing in keeping prostate tissue
healthy – it suppresses inflammation, which is a bad actor potentially driving
prostate cancer,” explained Dr. Lambert.
We must note this statement since we will show some contrary
versions later. They continue:
The road to understanding was not as clear in the
beginning. At first, Dr. Lambert’s group tested the theory that vitamin D
itself could be protective against prostate cancer in general. “When you take
Vitamin D and put it on prostate cancer cells, it inhibits their growth. But it
hasn’t been proven as an anti-cancer agent. We wanted to understand what genes
Vitamin D is turning on or off in prostate cancer to offer new targets.”
After the group identified GDF-15 upregulation as a
downstream result of vitamin D stimulation, they looked for GDF-15 in human
prostate cancer tissue samples. “We thought there might be high levels of
GDF-15 in normal tissue and low levels in prostate cancer, but we found that in
a large cohort of human prostate tissue samples, expression of GDF-15 did not
track with either normal or cancerous prostate tissue.”
Then they turned to immunohistochemistry and noticed a
pattern: GDF-15 protein expression was greater in samples with inflammatory
cells. It seemed GDF-15 was acting to suppress inflammation by inhibiting the
transcription factor NFkB. “There’s been a lot of work on inhibiting NFkB,”
said Dr. Lambert.
Since NFkB is well-studied, there may be a few new
potential treatments to explore for prostate cancer. “Now from this starting
point of vitamin D in prostate cancer, we’ve come a long way toward
understanding how we might use GDF-15 to target NFkB, which may have
implications in cancer types far beyond prostate.”
Now as NCBI states:
(GDF-15 is one of the) bone morphogenetic proteins are
members of the transforming growth factor-beta superfamily and regulate tissue
differentiation and maintenance. They are synthesized as precursor molecules
that are processed at a dibasic cleavage site to release C-terminal domains
containing a characteristic motif of 7 conserved cysteines in the mature
protein
In a similar fashion:
NF-κB (nuclear factor kappa-light-chain-enhancer of
activated B cells) is a protein complex that controls the transcription of DNA.
NF-κB is found in almost all animal cell types and is involved in cellular
responses to stimuli such as stress, cytokines, free radicals, ultraviolet
irradiation, oxidized LDL, and bacterial or viral antigens
From Zimmers et al we have a description of GDF-15:
The immunoregulatory cytokine macrophage inhibitory
cytokine-1 (MIC-1), a divergent TGF-beta family member, and its murine
ortholog, growth/differentiation factor-15 (GDF-15) are induced in hepatocytes
by surgical and chemical injury and heat shock. To better understand the in
vivo role this factor plays in organ injury, we examined the regulation of
GDF-15 in murine models of kidney and lung injury.
We demonstrate herein induction of GDF-15/MIC-1 after
surgical, toxic/genotoxic, ischemic, and hyperoxic kidney or lung injury. Gdf15
induction was independent of protein synthesis, a hallmark of immediate-early
gene regulation. Although TNF induced GDF-15 expression, injury-elicited Gdf15
expression was not reduced in mice deficient for both TNF receptor subtype.
Furthermore, although the stress sensor p53 is known to induce GDF-15/MIC-1
expression, injury-elicited Gdf15 expression was unchanged in p53-null mice.
Our results demonstrate that GDF-15 induction after organ injury is a hallmark
of many tissues. These data demonstrate that GDF-15/MIC-1 is an early mediator
of the injury response in kidney and lung that might regulate inflammation,
cell survival, proliferation, and apoptosis in a variety of injured tissues and
disease processes.
The GDF factor regulates the inflammatory and apoptotic
pathways in cells. Zimmers et al demonstrates several specific issues regarding
it regulatory effects.
As Vanhara et al state:
Deregulation of expression and function of cytokines
belonging to the transforming growth factor-β (TGF-β) family is often associated
with various pathologies. For example, this cytokine family has been considered
a promising target for cancer therapy. However, the detailed functions of
several cytokines from the TGF-β family that could have a role in cancer
progression and therapy remain unclear.
One of these molecules is growth/differentiation
factor-15 (GDF-15), a divergent member of the TGF-β family.
This stress-induced cytokine has been proposed to
possess immune-modulatory functions and its high expression is often associated
with cancer progression, including prostate cancer (PCa).
Now the above is possibly in contradiction to the
observation made in the most current paper. However, this work was done earlier
and the statement made is perhaps speculative at best.
However, studies clearly demonstrating the mechanisms for
signal transduction and functions in cell interaction, cancer progression and
therapy are still lacking. New GDF-15 roles have recently been identified for
modulating osteoclast differentiation and for therapy for PCa bone metastases.
Moreover, GDF-15 is as an abundant cytokine in seminal
plasma with immunosuppressive properties. We discuss studies that focus on the
regulation of GDF-15 expression and its role in tissue homeostasis, repair and
the immune response with an emphasis on the role in PCa development.
As Bruzzese et al note about the upregulation of GDF-15[5].
The tumor stroma is vital to tumor development,
progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the
abundant cell types in the tumor stroma, but the range of their contributions
to cancer pathogenicity has yet to be fully understood.
Here, we report a critical role for upregulation of the
TGFβ/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found
upregulated in situ and in primary cultures of CAF from prostate cancer.
Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects
on prostate cancer cell migration, invasion, and tumor growth.
Notably, GDF15-expressing fibroblasts exerted systemic in
vivo effects on the outgrowth of distant and otherwise indolent prostate cancer
cells. Our findings identify tumor stromal cells as a novel source of GDF15 in
human prostate cancer and illustrate a systemic mechanism of cancer progression
driven by the tumor microenvironment. Further, they provide a functional basis
to understand GDF15 as a biomarker of poor prognosis and a candidate
therapeutic target in prostate cancer.
Perhaps one may interpret the above in either way. Namely
GDF-15 upregulated may have been an attempt by the cell to reduce the imputed
inflammation of PCa. Now McCarty notes in the review of multiple targets for
PCa. First he discusses NF-κB:
Constitutive activation of the transcription factor NF-
κB has been observed in a high proportion of androgen-independent prostate
cancers. Presumably, the ability of NF-κB to promote transcription of the
prominent antiapoptotic protein Bcl-2aids the survival of cells that otherwise
would be at risk owing to loss of androgen activity. This constitutive
activation reflects increased activity of the IκB kinase (IKK) complex, but why
IKK is activated remains unclear. A report that dominant negative
NF-κB-inducing kinase (NIK) and tyrosine kinase inhibitors suppress the
constitutively elevated NF-κB activity in various prostate cancer cell lines
suggests that NIK, possibly downstream from a tyrosine kinase, may mediate the
constitutive activation of IKK.
Other factors suggested to play a role in the
constitutive activation of NF-κB in prostate cancer include 12-(S)-HETE, Id-1,
bombesin, and RhoA. In addition to suppressing apoptosis, NF-κB promotes malignant
behavior in other ways: stimulating transcription of cell cycle progression
factors (c-myc, cyclin D1), proteolytic enzymes (MMP-9, uPA), and angiogenic
factors (VEGF, IL-8). Thus, it is not surprising that nuclear localization of
NF-κB in prostate cancer biopsies has been shown to correlate with poor
clinical prognosis….
This is consistent with what we have shown before.
Normal prostate epithelium expresses vitamin D receptors,
and calcitriol, the natural agonist for these receptors, exerts a growth-inhibitory
effect.390-392 These cells also express 1-α-hydroxylase activity and thus can generate
their own calcitriol from circulating 25- hydroxycholecalciferol.391,393,394
Since the serum level of 25-hydroxycholecalciferol is determined largely by exposure
of skin to ultraviolet light, these findings have encouraged the speculation
that good vitamin D status might reduce prostate cancer risk. Although
epidemiological studies correlating assessed sunlight exposure with subsequent
prostate cancer risk are reasonably supportive of this thesis,395-401
prospective studies examining serum levels of calcitriol or 25- hydroxyvitamin
D have been much less so.402-407 Thus, the role of vitamin D status in prostate
cancer induction remains unclear. Since supra-physiological concentrations of
calcitriol have been employed in most in vitro studies, it is conceivable that
the growth inhibitory impact of this hormone on prostate epithelium is
pharmacological rather than physiological.
In the above by McCarty there is no clear nexus drawn
between NFκB and Vitamin D. The work in question regarding the nexus through
GDF-15 may have some promising results therefore.
Finally in a paper by
Jeet the authors discuss Vitamin D in murine models. They state:
The potential efficacy of vitamin D as a chemopreventive
agent for PC has been observed in large cohort studies of human patients with
PC [153, 154]. Based on these studies, precancerous and cancerous cohorts of
Nkx3.1; Pten compound mutant mice have been treated with 1α, 25
dihydroxyvitamin D3 (biologically active form of vitamin D3) for 4 months
continuously [155]. This results in a significant reduction in the occurrence
of HGPIN only in the precancerous cohort, whereas mice with already established
PIN lesions do not respond to this treatment. However, cancerous cohorts
display a less aggressive phenotype with small and focal lesions compared to
the wild type controls. Another study has used androgen-independent Gγ/T-15
transgenic mice to test the efficacy of EB1089 (a vitamin D3 analog) in
preventing prostate carcinogenesis [156]. Treatment of these mice with EB1089
at three different time points does not cause any significant reductions in
tumor onset or delay; however, tumor growth is adversely affected by 60% at a
higher dose of the compound albeit with attendant hypercalcemia and weight
loss.
We now show some of the pathways:
Now the specific pathway for what we have been discussing:
Now the presence of GDF-15 is as a specific activating
growth factor, GF, as shown in the above. Namely the activation moves down
through to NF-κB to activate cell survival and allow for proliferation.
Warburg Effect
The Warburg effect was proposed by Warburg in 1922 when
studying cancer. As Vender Heiden et al state in a recent review paper:
In contrast to normal differentiated cells, which rely
primarily on mitochondrial oxidative phosphorylation to generate the energy
needed for cellular processes, most cancer cells instead rely on aerobic
glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an
inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the
advantage it confers to cancer cells has been unclear.
Namely the alternate pathway is powerful yet confusing. As
Wang et al state in examining this effect in PCa:
The Warburg effect, the inefficient metabolic pathway
that converts glucose to lactate for rapid energy generation, is a phenomenon
common to many different types of cancer. This process supports cell
proliferation and promotes cancer progression via alteration of glucose,
glutamine and lipid metabolism. Prostate cancer is a notable exception to this
general process since the metabolic switch that occurs early during malignancy
is the reverse of the Warburg effect. This “anti-Warburg effect” is due to the
unique biology of normal prostate cells that harbor a truncated TCA cycle that
is required to produce and secret citrate.
In prostate cancer cells, the TCA cycle activity is
restored and citrate oxidation is used to produce energy for cancer cell
proliferation. 1,25(OH) 2 D 3 and androgen together modulates the TCA cycle via
transcriptional regulation of zinc transporters, suggesting that 1,25(OH) 2 D 3
and androgen maintain normal prostate metabolism by blocking citrate oxidation.
These data demonstrate the importance of androgens in the anti-proliferative
effect of vitamin D in prostate cancer and highlight the importance of
understanding the crosstalk between these two signaling pathways
Thus much of the analysis we have been discussing is good
science with some excellent observation based conjecture. However there is also
the dynamics of the Warburg effect that can be drawn into the analysis.
Observations
We can now make several observations about this continuing
investigation into Vitamin D and PCa. Lambert et al present an interesting
paradigm to consider in our understanding of PCa.
We leave with a few observation:
1. No clear benefit of Vitamin D enhancements seems to be
present. The data is still a bit confusing. On the one hand we have a trial
that says the lower the better the chance of not getting PCa and on the other hand
we have the statement that Vitamin D helps people with lesions as least in
murine models and petri dishes.
2. A logical pathway is presented. The GDF-15 path seems to
have a good logical basis and one approachable by targeted therapeutics. That
is always a benefit and can be helpful for many who have the problem.
3. Inflammation is a strong and viable source of a
precipitating event. This is a well-known observation and the relationship
between inflammation and PCa has always been strong. The use of NASIDS has been
observed as a putative preventive. The actual biochemical processes leading to
this need to be better understood.
4. HGPIN is reversible and this model should include such an
observation. Why does it reverse is an open question but its existence is
without question.
References
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2. Boland, M., et al, The effect of vitamin D supplementation on
skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis, The
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2014, doi:10.1016/S2213-8587(13)70212-2
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published online: 18 OCT 2014 DOI: 10.1002/pros.22911
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15. Wong et al, In Older Men, Lower Plasma 25-Hydroxyvitamin D Is
Associated with Reduced Incidence of Prostate, but Not Colorectal or Lung
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