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Bone marrow derived stem cells in normal physiology and in cancer.

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Bone marrow derived stem cells in normal physiology and in cancer. An introduction Stem cells exist in the normal bone marrow that can engraft in endothelial ... – PowerPoint PPT presentation

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Title: Bone marrow derived stem cells in normal physiology and in cancer.


1
Bone marrow derived stem cells in normal
physiology and in cancer. An introduction
2
Association between Cardiovascular Risk Factors
and Endothelial-Progenitor-Cell Colony Counts
Hill, J. M. et al. NEJM 2003348593-600
3
Survival analyzed for cardiovascular death
compared to levels of CD34, KDR, circulating
endothelial progenitor cells
Werner N, Kosiol S. et al. NEJM 2005353999-1007
4
Intra-coronary autologous bone marrow cell
transfer after myocardial infarction. The BOOST
randomised controlled trial.
60 patients randomized 11 Given approximately
9x106 CD34 cells via injection in coronary artery
Wollert KC, Meyer GP, et al. Lancet 2004 364
141-148
5
Intra-coronary autologous bone marrow cell
transfer after myocardial infarction. The BOOST
randomised controlled trial.
Wollert KC, Meyer GP, et al. Lancet 2004 364
141-148
6
Intra-coronary autologous bone marrow cell
transfer after myocardial infarction. The BOOST
randomised controlled trial.
4 of 5 outcome measure indicators showed no
change.
Wollert KC, Meyer GP, et al. Lancet 2004 364
141-148
7
REVIVAL2 Stem cell mobilization by
granulocyte-colony stimulating factor for
patients with acute myocardial infarction. A
randomized, controlled trial.
114 patients randomized 11 Given G-CSF
standard care 10 fold increase in circulating
endothelial cells after 1 week
Zohlnhoefer D, Ott I, et al. JAMA 2006 295
1003-1010
8
REVIVAL2 Stem cell mobilization by
granulocyte-colony stimulating factor for
patients with acute myocardial infarction. A
randomized, controlled trial.
Zohlnhoefer D, Ott I, et al. JAMA 2006 295
1003-1010
9
Stem cells and differentiation in the
hematopoietic lineage
Zipori D. Stem Cells 2005 23 719-726
10
Stem state Plasticity is essential, self
renewal and hierarchy are optional.
Zipori D. Stem Cells 2005 23 719-726
11
Transplanted bone marrow generates new neurons in
human brains
Mezey, Vogelsang, et al. PNAS 2003 100 1364-1369
Autopsy material was studied from 4 female
patients who had bone marrow transplant from male
donors for leukemia and died months to years
after the transplant. Each 6 micron section of
brain was stained with 3 immunofluorescent
reagents marking Y chromosome, neural
differentiation, and cell nucleus.
12
Mezey, Vogelsang, et al. PNAS 2003 100 1364-1369
A 6-µm-thin section from somatosensory cortex of
patient 2 demonstrates the presence of the Y
chromosome depicted as red dots and viewed
through a rhodamine filter. The immunostaining
for the neuronal marker NeuN in green (B), and
the UV filter shows all cell nuclei in blue after
staining with 4',6-diamidino-2-phenylindole, a
chromosomal stain (C). (D) The overlay of the
three filters, where arrows point to cells that
carry all markers, indicating that they derived
from the donor bone marrow (Y chromosome
positive) and bear the specific neuronal marker
NeuN. Arrowheads point at nonneuronal
donor-derived cells. (Scale bars, 10 µm.)
13
Liver from bone marrow in humans
Theise ND, Krause DS, et al. Hepatology 2000 32
11 - 16
Liver biopsies of male recipients of liver
transplants from female donors Slides examined
and photographed with IHC to identify hepatocytes
and cholangiocytes, then restained with FISH to
identify X and Y chromosomes
14
Liver from bone marrow in humans
Theise ND, Krause DS, et al. Hepatology 2000 32
11 - 16
Immuno for CK 8, 18, 19
Red X chromosome Turquoise Y chromosome Blue
is DAPI
15
Liver from bone marrow in humans
Theise ND, Krause DS, et al. Hepatology 2000 32
11 - 16
Immuno for CK 8, 18, 19
Red X chromosome Turquoise Y chromosome Blue
is DAPI
16
Increased chimerism of bronchial and alveolar
epithelium in human lung allografts undergoing
chronic injury
Kleeberger W, Versmold A, et al. Am J Path 2003
162 1487 - 1494
Laser-capture microdissected samples of tissue
from transplanted lung in gender-mismatched
cases. PCR used to quantitate X and Y chromosome
to measure chimerism.
17
Transplanted lung with chronic inflammation and
squamous metaplasia
Transplanted lung with normal bronchial glands
Recipient genotype by short tandem repeat PCR
Donor and recipient genotype detected
Lesser degree of chimerism
Kleeberger W, Versmold A, et al. Am J Path 2003
162 1487 - 1494
18
Progenitor cells from bone marrow can migrate
into blood vessels, liver, myocardium, and
brain. BMDCs can differentiate and incorporate
at site of implantation. This process is more
extensive if there is chronic inflammation at the
site. Homing and implantation may be controlled
by expression of specific integrins and may
require the the stimulus of VEGF. This
physiologic process has not yet been used
therapeutically.
19
Biofluorescence in Aequorea victoria
20
Fluorescent proteins from Aequorea and Anthozoa
do not require cofactors or ATP Intrinsic
luminescence is 1,000 fold greater than luciferin
Verkuosha, Lukyanov. Nature Biotechnology 2004
22 289-296
21
Fluorescent proteins can be transfected into a
wide variety of tissues and organisms with
genetic control of expression.
Verkuosha, Lukyanov. Nature Biotechnology 2004
22 289-296
22
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23
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24
A metastasis in lung composed of cells from 2
different clones of fibrosarcoma
Hoffman, R. Nature Reviews Cancer 2005 5 796-806
25
Id mouse model of CEP cells in tumor angiogenesis
Id protein deficient mice are resistant to the
growth of transplanted tumors Susceptibility
returns with transplantation of normal bone
marrow or VEGF-mobilized circulating endothelial
precursor cells
Lyden D, Hattori K, et al. Nature Medicine 2001
7 1194-1201
26
Id mouse model of CEP cells in tumor angiogenesis
Lyden D, Hattori K, et al. Nature Medicine 2001
7 1194-1201
27
Id mouse model of CEP cells in tumor angiogenesis
Transplanted LacZ bone marrow cells forming a
blood vessel in a tumor in an Id1/-Id3-/- mouse
Lyden D, Hattori K, et al. Nature Medicine 2001
7 1194-1201
28
Id mouse model of CEP cells in tumor angiogenesis
The effect of transplanting Id- animal with
normal bone marrow is blocked if treated with
antibody against VEGF receptor.
Lyden D, Hattori K, et al. Nature Medicine 2001
7 1194-1201
29
Id mouse model of CEP cells in tumor angiogenesis
Tumor growth requires participation of
endothelial precursor cells mobilized from the
bone marrow by VEGF (vascular endothelial growth
factor)
Lyden D, Hattori K, et al. Nature Medicine 2001
7 1194-1201
30
Homing of bone-marrow derived cells in tumor
angiogenesis
Sections of N202 breast cancer growing in a nu/nu
mouse with injected with GFP, CD34 bone marrow
cells
Jin, Aiyer, et al. J Clin Invest Mar 2006 116
652-662
31
Homing of bone-marrow derived cells in tumor
angiogenesis
In this system, homing of bone marrow cells
depends on expression of ?4?1 integrin
(VLA-4). The bone marrow-derived cells
differentiate into endothelial cells within the
growing tumor.
Jin, Aiyer, et al. J Clin Invest Mar 2006 116
652-662
32
Homing of bone marrow-derived precursors cells
before tumor metastasis
Kaplan R N, Lyden D, et al. Nature Dec 2005 438
820-827
33
Homing of bone marrow-derived precursors cells
before tumor metastasis
Lung following bone marrow transplant, before
injection of melanoma cells
Lung day 14 after injection of melanoma cells
Kaplan R N, Lyden D, et al. Nature Dec 2005 438
820-827
34
Homing of bone marrow-derived precursors cells
before tumor metastasis
Lung day 23 after injection of melanoma cells
Lung day 18 after injection of melanoma cells
Kaplan R N, Lyden D, et al. Nature Dec 2005 438
820-827
35
Bone marrow transplant with male donor, female
recipient
C57BL/6 ROSA26 eGFP Cells express GFP and
non-mammalian beta-galactosidase
36
C57BL/6 mouse transplanted with GFP, ?-gal bone
marrow or wild-type marrow
Infected with Helicobacter
Gastric muscosa assayed for GFP,
beta-galactosidase
37
Immunohistochemical stain for beta-galactosidase
in in dysplastic gastric glands with chronic
Helicobacter infection. In C note
beta-galactosidase in cytoplasm of adipocyte.
Li, Houghton, et al. W. J. Gastroenterology.
2006 12(3) 363-371
38
Li, Houghton, et al. W. J. Gastroenterology.
2006 12(3) 363-371
39
ROSA26,eGFP marrow
Wild-type marrow
Gastric glands with intra-epithelial neoplasia
with immunofluorescence for cytokeratin (green)
and beta-galactosidase (red).
Houghton, Stoicov, et al. Science. 2004 306
1568-71
40
Tumor cells in gastric carcinoma (black nuclei)
with Y chromosome by FISH (green) in cells with
cytokeratin immunofluorescence (red).
Houghton, Stoicov, et al. Science. 2004 306
1568-71
41
  • Stem cells exist in the normal bone marrow that
    can engraft in endothelial, mesenchymal, and
    epithelial tissues.
  • The cytokine and integrin signals that control
    mobilization, tissue homing, engraftment,
    proliferation, and differentiation are not fully
    known.

42
  • Engraftment of normal tissues by bone marrow
    derived stem cells may be permissive or required
    for tumor metastasis.
  • Sites of engraftment following chronic
    inflammation may be vulnerable to malignant
    transformation.
  • Tumors in solid tumors may arise in stem cells
    in tissue derived from bone marrow.

43
  • Thank you.

James.Strauss_at_usoncology.com
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