|
Search for our Investigators on Pub
Med
|
PATRICIA A. WOOD, M.D., Ph.D.
Hrushesky
WJM, You S, Du-Quiton J, Xiong Y, Li M, Ohmori M, Wood, P.
Circadian cancer biology: Does the time of day we treat
matter? Basic and Clinical Medicine 25(4): 289-330, 2005.
No abstract available.
Wood PA, Bove K, You S, Chambers A,
Hrushesky WJ. Cancer growth and spread are saltatory and
phase-locked to the reproductive cycle through mediators of
angiogenesis. Mol Cancer Ther. 2005 Jul;4(7):1065-75.
The frequency of breast cancer metastatic
spread is affected by the menstrual cycle phase of its
resection. Breast cancer growth, post-resection spread, and
cure frequency are each modulated by the estrous cycle in
C(3)HeB/FeJ mice. Tumor metastases are 2- to 3-fold more
frequent when the resection is done during diestrus as
compared with estrus. Tumor angiogenesis is essential for
both cancer growth and lethal metastatic cancer spread. The
balance between vascular endothelial growth factor (VEGF)
and basic fibroblast growth factor (bFGF) modulates new
blood vessel formation and blood vessel permeability. Sex
hormones modulate the expression of these key angiogenesis
regulators in the endometrium and uterus. We, therefore,
asked whether the estrous cycle modulates the density of
CD31-positive vessels within the tumor, the permeability of
tumor blood vessels, levels of VEGF and bFGF immunoreactive
protein in normal breast and breast cancer, and whether
expression of these genes are modulated by the estrous cycle
stage in C(3)HeB/FeJ mice. We find that tumor blood vessel
density and blood volume do not vary throughout the cycle;
however, tumor capillary permeability is regulated by the
estrous cycle being highest in diestrus, the cycle stage
associated with the highest cancer growth rate and the
highest frequency of post-resection cancer metastasis. VEGF
protein levels in breast cancer are >100-fold higher than in
normal breast. VEGF protein in this mammary tumor varies
with the estrus cycle with highest levels in proestrus. In a
non-breast tumor, methylcholantrenene A sarcoma, from
CD(2)F(1) mice, tumor VEGF protein also varies with the
estrus cycle with highest levels in proestrus and diestrus.
VEGF gene expression in the mammary tumor does not change
significantly across the cycle, but is modulated by the
cycle in normal breast tissue. bFGF protein concentration is
6-fold higher in normal breast than in breast cancer. bFGF
protein pattern in both tumor and breast are similar,
opposite to VEGF, and affected by oophorectomy. bFGF message
is modulated by the cycle in both breast cancer and normal
breast. The changes in breast cancer capillary permeability,
VEGF, and bFGF that occur during each fertility cycle, in
breast tissue and breast cancer, putatively in response to
cyclical changes in sex hormones, might contribute, at least
in part, to both the modulation of cancer growth and
post-resection breast cancer spread by the fertility cycle.
These fertility cycle-induced effects on tumor biology also
seem to extend to non-breast cancer biology.
Wood PA, Hrushesky WJ. Sex cycle
modulates cancer growth. Breast Cancer Res Treat. 2005
May;91(1):95-102.
HYPOTHESIS: Among premenopausal women,
both post-resection metastatic potential and tumor growth
rate are influenced by the menstrual cycle. There is strong
support for the former in large retrospective studies of
surgical resection timing within the menstrual cycle and the
following experiments were conducted to critically evaluate
the latter. METHODS: We studied a transplantable breast
cancer of C3HeB/FeJ mice (3 studies), and a transplantable
methylcholantherene A induced sarcoma of CD2F1 mice (2
studies). We concurrently measured local cancer size and
estrous cycle stage up to twice and at least once each day.
There is a natural individual variability in the average
length of normal estrus (3-1/2 to 7 days) cycle in mice. We
assessed the effect of the cycle stage and cycle duration on
tumor size. RESULTS: We found identical estrous cycle stage
coordination of cancer size, and identical effects of
cycling frequency across all studies in each of these two
tumors, both of which express both estrogen receptor alpha
and progesterone receptor. Little or no change in cancer
size occurs during proestrus (preovulatory phase) and estrus
(periovulatory phase); tumor size increases several fold
during diestrus (post-ovulatory phase); and the tumor
shrinks partially as the next proestrus phase is approached.
Across both mouse strains and tumor types, mice whose
average cycle length is briefer (faster cyclers), have
slower average tumor growth rate than those with longer
cycles (slower cyclers) who have faster tumor growth rates.
CONCLUSION: The virtually identical modulation of tumor size
and cancer growth rate, in each of two very different
transplantable cancers (one, classically
sex-hormone-dependent, and the other, never previously
recognized as hormone dependent) growing in two unrelated
inbred mouse strains, indicates that the fertility cycle
related host factors affect cancer size and growth rate.
These experimental findings suggest that cancer cell
proliferation of both breast and non-breast cancers in
premenopausal women may be meaningfully coordinated by the
menstrual cycle. If this proves to be the case, then any
therapeutic strategy targeting proliferating cancer cells
should be most effective against cancer of cycling women
when given during the follicular phase of their menstrual
cycles.
You S, Wood PA, Xiong Y, Kobayashi M,
Du-Quiton J, Hrushesky WJ. Daily coordination of cancer
growth and circadian clock gene expression. Breast Cancer
Res Treat. 2005 May;91(1):47-60.
BACKGROUND: Circadian coordination in
mammals is accomplished, in part, by coordinate, rhythmic
expression of a series of circadian clock genes in the
central clock within the suprachiasmatic nuclei (SCN) of the
hypothalamus. These same genes are also rhythmically
expressed each day within each peripheral tissue. METHODS:
We measured tumor size, tumor cell cyclin E protein, tumor
cell mitotic index, and circadian clock gene expression in
liver and tumor cells at six equispaced times of day in
individual mice of a 12-h light, 12-h dark schedule.
RESULTS: We demonstrate that C3HFeJ/HeB mice with
transplanted syngeneic mammary tumor maintain largely normal
circadian sleep/activity patterns, and that the rate of
tumor growth is highly rhythmic during each day. Two daily
2.5-fold peaks in cancer cell cyclin E protein, a marker of
DNA synthesis, are followed by two daily up-to-3-fold peaks
in cancer cell mitosis (one minor, and one major peak).
These peaks are, in turn, followed by two prominent daily
peaks in tumor growth rate occurring during mid-sleep and
the second, during mid-activity. These data indicate that
all therapeutic targets relevant to tumor growth and tumor
cell proliferation are ordered in tumor cells within each
day. The daily expression patterns of the circadian clock
genes Bmal1, mPer1, and mPer2, remain normally circadian
coordinated in the livers of these tumor bearing mice. Bmal1
gene expression remains circadian rhythmic in cancer cells,
although damped in amplitude, with a similar circadian
pattern to that in normal hepatocytes. However, tumor cell
mPer1 and mPer2 gene expression patterns fail to maintain
statistically significant daily rhythms. CONCLUSION: We
conclude that, if core circadian clock gene expression is
essential to gate tumor cell proliferation within each day,
then there may be substantial redundancy in this timing
system. Alternatively, the daily ordering of tumor cell
clock gene expression may not be essential to the daily
gating of cancer cell DNA synthesis, mitosis and growth.
This would indicate that host central SCN-mediated
neuro-humoro-behavioral controls and/or daily light-induced
changes in melatonin or peripherally-induced rhythms such as
those resulting from feeding, may be adequate for the daily
coordination of cancer cell expression of proliferation
related therapeutic targets.
Hrushesky W, You W, Du-Quiton J, Li M,
Ohmori M, Wood P. Circadian Cancer Biology: Does the Time of
the Day We Treat Matter? Journal of Basic and Clinical
Medicine; 25(4):289-330, April 2005.
No abstract available.
Hrushesky W, Wood P, Levi F, von
Roemeling R, Bjarnason G, Focan C, Meier K, Cornelissen G,
Halberg F. A recent illustration of some essentials of
circadian chronotherapy study design. J Clin Oncol. 2004 Jul
15;22(14):2971-2; author reply 2972.
No abstract available.
You S, Li W, Kobayashi M, Xiong Y,
Hrushesky W, Wood P. Creation of a stable mammary tumor cell
line that maintains fertility-cycle tumor biology of the
parent tumor. In Vitro Cell Dev Biol Anim. 2004
Jul-Aug;40(7):187-95.
A mammary tumor cell line, designated
MTCL, was successfully established from a mouse primary
mammary tumor (MTP). The MTCL cells retain cytokeratin and
both estrogen receptor (ER) and progesterone receptor (PR)
in vitro. In vitro exposure of MTCL cells to progesterone
causes a decrease in the cellular (3)H-thymidine uptake,
indicating an inhibition by progesterone on MTCL cellular
deoxyribonucleic acid synthesis, whereas exposure of the
cells to a high dose of estrogen (15 pg/ml) for 48 h causes
an increase of (3)H-thymidine uptake. We inoculated both MTP
or MTCL tumor cells into normal cycling female C(3)HeB/FeJ
mice and demonstrated that the post-resection metastatic
recurrence of MTCL tumors, like the original MTP tumors,
depends on the time of tumor resection within the mouse
estrous-cycle stage. Both MTCL and MTP tumors have similar
histological appearances with the exception of less
extensive tumor necrosis and higher vascularity in MTCL
tumors. Equivalent levels of sex hormone receptors (ER
alpha, ER beta, and PR), epithelial growth hormone receptors
(Her2/neu, EGFR1), tumor suppressors (BRCA1, P53), and cell
apoptosis-relevant protein (bcl-xl) were found in these in
vivo tumors by immunohistochemistry. Cyclin E protein,
however, was significantly higher in MTP tumors compared
with MTCL tumors. Our results indicate that MTCL cells
retain many of the biologic features of the original MTP
primary tumor cells, and to our knowledge, it is the first
in vitro cell line that has been shown to maintain the
estrous-cycle dependence of in vivo cancer metastasis.
For more publications,
click here. |
Pat Wood's information page
|
