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CXCR4 receptor is correlated to the development of metastases in leiomyosarcoma, pleomorphic sarcoma and
liposarcoma
S.C.D.U. Medical Oncology S.C.D.U. Medical Oncology I.R.C.C. CandioloI.R.C.C. Candiolo
Ordine MaurizianoOrdine Mauriziano
S Aliberti, G Grignani, G Cavalloni, A Pisacane, P Allione,I Sarotto, Y Pignochino, M Motta, B Torchio, M Risio, M Aglietta.
“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%)
Cancer cell
YY
chemokine receptor
chemokine
endothelium
Non-target tissue
Cancer cell
Y Yendothelium
differentchemokine
Target tissue
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
Involvement of CXCR4/SDF-1 system in cancer progression
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 ofCXCR4, EGFR and angioinvasiveness features onprimary 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.
CXC4 immunohistochemistry
CXCR4: Pharmagin 12G-5 monoclonal antibody
Cytoplasmic positivity Nuclear positivity
EGFR immunohistochemistry
EGFR: pharmaDx monoclonal antibody DakoCytomation
Positive = 3+ & 80% of cells Negative = 0/1+ & < 1% of cells
Results
Negative 34/67
50.7%
Positive 33/67
49.3%
Negative 29/67
43.2%
Low 19/67
28.4%
High 19/67
28.4%
Negative 13/67
19.4%
Low 12/67
17.9%
High 42/67
62.7%
CXCR4 EGFRAngio-
Invasiveness
Variable
CXCR4
EGFR
Angiogenesis
Grading
T
Tumor burden
0.07
0.05
0.018
0.32
0.017
Univariate
0.067
0.03
0.06
0.02
Multivariate
Correlation with development of metastases
Response according to metastasisCumulativ e Proportion Surv iv ing (Kaplan-Meier)
Complete Cens ored
0 50 100 150
Time
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Cum
ulative Proportion S
urviving
p = .00645
CXCR4 ne g
CXCR4 pos
Cumulativ e Proportion Surv iv ing (Kaplan-Meier)
Complete Cens ored
0 20 40 60 80 100 120
Time
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Cum
ulative Proportion S
urviving
CXCR4 - stratified by grading
CXCR4 pos p = 0.018
CXCR4 neg
Cumulativ e Proportion Surv iv ing (Kaplan-Meier)
Complete Cens ored
0 20 40 60 80 100 120
Time
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Cum
ulative Proportion S
urviving
CXCR4 neg
CXCR4 pos
p = 0.05
Grade = 1 or 2 Grade = 3
CXCR4 expression on leiomyosarcoma cell lines
Cell line % CXCR4+ cells
SK-LMS-1
Leiomyosarcoma
20-70%
SK-UT-1
Leiomyosarcoma
20-70%
MES-SA Uterine leiomyosarcoma
10-12%
91266 Uterine leiomyosarcoma
Negative
0
5
10
15
20
25
30
35
40
45
SK-LMS-1-25 SK-LMS-1-50 SK-UT-1-25 SK-UT-1-50
NT SDF-1 1 h 100 ng ml
CXCR4 down-regulation by SDF-1 on CXCR4+ leiomyosarcoma cell lines
• 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.
Conclusions
Recommended