Transcript Tumor progression in osteosarcoma: role of CXCR4/SDF

CXCR4 receptor is correlated to the development of
metastases in leiomyosarcoma, pleomorphic sarcoma and
liposarcoma
S Aliberti, G Grignani, G Cavalloni, A Pisacane, P Allione,
I Sarotto, Y Pignochino, M Motta, B Torchio, M Risio, M Aglietta.
S.C.D.U. Medical Oncology
I.R.C.C. Candiolo
Ordine Mauriziano
“When a plant goes to seed, its
seeds are carried in all directions;
but they can only live and grow if
they fall on congenial soil.”
S Paget The Lancet 1889
-3149 adult patients with soft tissue sarcoma were admitted
and treated at Memorial Sloan-Kettering Cancer Center.
-719 patients developed lung metastases (about 24%)
Tumor progression steps
Target tissue
Non-target tissue
endothelium
endothelium
chemokine
different
chemokine
chemokine
receptor
Y
Y
Cancer cell
Cancer cell
Involvement of CXCR4/SDF-1 system
in cancer progression
Pancreatic cancer
Kosshiba et al., Clin. Cancer Res. 2000
Neuroblastoma
Geminder et al., J. Immunol. 2001
Breast cancer
Muller et al., Nature 2001
Rhabdomyosarcoma
Libura et al., Blood 2002
Prostate cancer
Taichman et al., Cancer Res. 2002
Colon cancer
Zeelemberg et al., Cancer Res. 2003
Osteosarcoma
Perissinotto et al., Clin Cancer Res. 2005
Laverdiere et al., Clin Cancer Res. 2005
Non-small cell lung cancer cells
Su et al., Clin Cancer Res. 2005
Esophageal cancer
Kaifi et al., J Natl Cancer Inst. 2005
Carcinomatosis of Gastric Cancer
Yasumoto et al., Cancer Res. 2006
Glioma
Ehtesham et al., Oncogene 2006
Melanoma
Bartolome et al., Cancer Res. 2006
Purpose
• To analyze expression patterns of CXCR4,
EGFR, angioinvasiveness (by standard
immunohistochemical technique) along with
other primary tumor features (T and grading).
• To assess if there is a correlation among the
characteristics of primary tumor and the
development of metastases.
Materials and methods
We retrospectively evaluated expression patterns of
CXCR4, EGFR and angioinvasiveness features on
primary tumors in 67 pts.
-Mean age = 57 yrs (24 - 85)
-Male/female = 38/29
-Median follow-up = 57 mos (2 – 160)
-Limbs/retroperitoneal = 47/20
-Histotype: leiomyosarcoma, pleomorphic sarcoma
non-myxoid liposarcoma.
-Grading: according to Coindre et al.
Materials and methods
Site
N°
Lung
13
40%
Lung +
other
Liver
11
18%
6
18%
Other
3
9%
CXC4 immunohistochemistry
Cytoplasmic positivity
Nuclear positivity
CXCR4: Pharmagin 12G-5 monoclonal antibody
EGFR immunohistochemistry
Positive = 3+ & 80% of cells
Negative = 0/1+ & < 1% of cells
EGFR: pharmaDx monoclonal antibody DakoCytomation
Angioinvasiveness features
Results
CXCR4
EGFR
Negative 13/67
19.4%
Low
12/67
17.9%
High
42/67
62.7%
Negative 29/67
43.2%
Low
19/67
28.4%
High
19/67
28.4%
AngioInvasiveness
Negative 34/67
50.7%
Positive
33/67
49.3%
Correlation with development
of metastases
Variable
Univariate Multivariate
CXCR4
0.017
0.02
EGFR
0.32
Angiogenesis
0.018
0.06
Grading
0.05
0.03
T
0.07
Tumor
burden
0.067
Response according to metastasis
Cumulative Proportion Surviving (Kaplan-Meier)
Complete
Censored
1,0
0,9
0,8
0,7
0,6
CXCR4 neg
0,5
Cumulative Proportion Survivin
0,4
p = .00645
0,3
CXCR4 pos
0,2
0
50
100
Time
150
CXCR4 - stratified by grading
Cumulative Proportion Surviving (Kaplan-Meier)
Complete
Cumulative Proportion Surviving (Kaplan-Meier)
Censored
Complete
Censored
1,0
1,0
0,9
0,8
0,9
CXCR4 neg
0,7
0,8
0,6
0,5
0,7
p = 0.05
0,4
0,6
CXCR4 neg
0,3
0,4
0
20
40
60
80
Time
Grade = 1 or 2
100
120
Cumulative Proportion Surviving
Cumulative Proportion Surviving
CXCR4 pos
0,5
0,2
CXCR4 pos
0,1
p = 0.018
0,0
0
20
40
60
Time
Grade = 3
80
100
120
Where do we go from here?
CXCR4 expression on
leiomyosarcoma cell lines
Cell line
SK-LMS-1
Leiomyosarcoma
SK-UT-1
Leiomyosarcoma
MES-SA Uterine
leiomyosarcoma
91266 Uterine
leiomyosarcoma
% CXCR4+
cells
20-70%
20-70%
10-12%
Negative
CXCR4 down-regulation by SDF-1 on
CXCR4+ leiomyosarcoma cell lines
45
40
35
30
25
20
15
10
5
0
SK-LMS-1-25
SK-LMS-1-50
NT
SK-UT-1-25
SDF-1 1 h 100 ng ml
SK-UT-1-50
Regulation of CXCR4 expression by in vitro
gene transduction in leiomyosarcoma cell line
AMD3465 selectively reduces CXCR4 transcript
expression in lungs.
Conclusions
• In this retrospective series we show how CXCR4 is
associated with the development of lung metastases.
• We are currently verifying these results on larger
series.
• We are developing an in vitro model in which we can
modulate CXCR4 expression.
• The metastatic behavior of these histotypes needs
further study but we believe CXCR4 may play a role
in the recurrence of soft tissue sarcoma.
Acknowledgments
Medical Oncology:
Sandra Aliberti
Paolo Allione
Massimo Aglietta
Surgical Pathology:
Alberto Pisacane
Ivana Sarotto
Mauro Risio
Surgical Pathology:
Manuela Motta
Bruno Torchio
Molecular Oncology: Giuliana Cavalloni
Ymera Pignochino