Page 315 - 2014 Printable Abstract Book
P. 315
with DKK-1. Conclusion: Wnt5a is overexpressed in lymph node metastatic OSCC. Our data suggests that
Wnt5a signals through non-canonical Jnk signaling to result in OSCC cell invasion in OSCC cells. Ongoing
studies are aimed at characterizing the specific role of Wnt5a in activating Jnk signaling in OSCC cells, and
studying pathway inhibition in preclinical models. Inhibition of Wnt5a/Jnk signaling may lead to reduced
lymph node metastasis in OSCC and improved prognosis.
(PS5-49) TGFβ from bone marrow derived cells (BMDC) conveys radiation resistance in lung cancer.
1
2
2
2
3
Shisuo Du ; Ilenia Pellicciotta ; Chen-Hao Lo ; Renate Parry ; and Mary Helen Barcellos-Hoff , New York
1
2
University, New York, NY ; New York University School of Medicine, New York, NY ; and Varian Medical
3
Systems, Inc.,, Menlo Park, CA
Activation of the TGFβ signaling pathway in cancer cells promotes various mechanisms of
resistance to radiotherapy (RT). Here we show that TGFβ production by bone marrow derived cells
(BMDC) compromises tumor response to radiotherapy. Lewis lung carcinoma (LLC) cells grown as sub-
cutaneous tumors in syngeneic C57/bl6 mice were treated with 5 fractions of 6 Gy with and without TGFβ
neutralizing antibody 1D11, administered 24 hr before, during, and subsequent till termination (~ 2
weeks). Tumors treated with 1D11 alone showed no growth delay compared to control antibody, while
irradiated tumors treated with 1D11 showed significantly (p=0.02) better tumor control (460±68 mm3)
compared to RT alone (743±72 mm3) at termination. Notably, recruitment of CD11b+ BMDC during
irradiated tumor re-growth was prevented by 1D11. Moreover, CD11b+ BMDC appear to activate TGFβ
within the tumor, but not in distant organs, and that TGFβ was markedly higher in BMDC than adjacent
LLC cells. We tested the contribution of these cells by treating mice with AMD3100, which is an FDA
approved SDF-1/CXCR4 signaling inhibitor, and compared the therapeutic effect to TGFβ blockade.
Surprisingly AMD3100 and 1D11 similarly improved control of irradiated tumors. This led us to postulate
that CD11b+ cells are a source of TGFβ necessary for tumor regrowth. Mice treated with both agents in
the context of RT provided no additional growth delay over the single agent. These data suggest that since
BMDC are major source of TGFβ, suppressing BMDC recruitment presented same biologic effect as
neutralizing TGFβ ligand. To further test this hypothesis, we established subcutaneous LLC tumors in Tgfb1
heterozygote C57/bl6 mice in which all stroma components express lower TGFβ. LLC tumors grew with
similar kinetics in Tgfb1 heterozygote and wildtype mice. Consistent with pharmacologic inhibition TGFβ
using 1D11, genetically depleting stromal TGFβ potently augmented the response to RT. These data
indicate that BMDC/stromal-derived TGFβ confers microenvironment-mediated resistance in lung cancer
and support TGFβ as an emerging target for pharmacological modulation in radiotherapy.
(PS5-50) Circulating microparticles associate to severe radiation proctitis consecutive to abdomino-
1
1
1
pelvic radiotherapy. Stephane Flamant, PhD ; Alexandre Ribault ; Sophie Jacob, PhD ; Claire Squiban ;
1
3
4
2
3
Laurent Arnaud, PhD ; Aurélie Leroyer, PhD ; Florence Sabatier, MD, PhD ; Jean-Marc Simon, MD ; Marc
1
Benderitter, PhD ; and Radia Tamarat, PhD ; IRSN, Fontenay-aux-Roses, France ; CHU la Conception,
1
1
2
Marseille, France ; INSERM UMR-1076, Marseille, France ; and CHU La Pitié-Salpétrière, Paris, France
4
3
Microparticles (MPs) are membrane fragments with biological activities shed from damaged or
activated cells. MPs have been studied as biomarkers in several inflammatory diseases and as central
players in intercellular communication. In this study we investigated the potential use of MPs as
313 | P a g e
Wnt5a signals through non-canonical Jnk signaling to result in OSCC cell invasion in OSCC cells. Ongoing
studies are aimed at characterizing the specific role of Wnt5a in activating Jnk signaling in OSCC cells, and
studying pathway inhibition in preclinical models. Inhibition of Wnt5a/Jnk signaling may lead to reduced
lymph node metastasis in OSCC and improved prognosis.
(PS5-49) TGFβ from bone marrow derived cells (BMDC) conveys radiation resistance in lung cancer.
1
2
2
2
3
Shisuo Du ; Ilenia Pellicciotta ; Chen-Hao Lo ; Renate Parry ; and Mary Helen Barcellos-Hoff , New York
1
2
University, New York, NY ; New York University School of Medicine, New York, NY ; and Varian Medical
3
Systems, Inc.,, Menlo Park, CA
Activation of the TGFβ signaling pathway in cancer cells promotes various mechanisms of
resistance to radiotherapy (RT). Here we show that TGFβ production by bone marrow derived cells
(BMDC) compromises tumor response to radiotherapy. Lewis lung carcinoma (LLC) cells grown as sub-
cutaneous tumors in syngeneic C57/bl6 mice were treated with 5 fractions of 6 Gy with and without TGFβ
neutralizing antibody 1D11, administered 24 hr before, during, and subsequent till termination (~ 2
weeks). Tumors treated with 1D11 alone showed no growth delay compared to control antibody, while
irradiated tumors treated with 1D11 showed significantly (p=0.02) better tumor control (460±68 mm3)
compared to RT alone (743±72 mm3) at termination. Notably, recruitment of CD11b+ BMDC during
irradiated tumor re-growth was prevented by 1D11. Moreover, CD11b+ BMDC appear to activate TGFβ
within the tumor, but not in distant organs, and that TGFβ was markedly higher in BMDC than adjacent
LLC cells. We tested the contribution of these cells by treating mice with AMD3100, which is an FDA
approved SDF-1/CXCR4 signaling inhibitor, and compared the therapeutic effect to TGFβ blockade.
Surprisingly AMD3100 and 1D11 similarly improved control of irradiated tumors. This led us to postulate
that CD11b+ cells are a source of TGFβ necessary for tumor regrowth. Mice treated with both agents in
the context of RT provided no additional growth delay over the single agent. These data suggest that since
BMDC are major source of TGFβ, suppressing BMDC recruitment presented same biologic effect as
neutralizing TGFβ ligand. To further test this hypothesis, we established subcutaneous LLC tumors in Tgfb1
heterozygote C57/bl6 mice in which all stroma components express lower TGFβ. LLC tumors grew with
similar kinetics in Tgfb1 heterozygote and wildtype mice. Consistent with pharmacologic inhibition TGFβ
using 1D11, genetically depleting stromal TGFβ potently augmented the response to RT. These data
indicate that BMDC/stromal-derived TGFβ confers microenvironment-mediated resistance in lung cancer
and support TGFβ as an emerging target for pharmacological modulation in radiotherapy.
(PS5-50) Circulating microparticles associate to severe radiation proctitis consecutive to abdomino-
1
1
1
pelvic radiotherapy. Stephane Flamant, PhD ; Alexandre Ribault ; Sophie Jacob, PhD ; Claire Squiban ;
1
3
4
2
3
Laurent Arnaud, PhD ; Aurélie Leroyer, PhD ; Florence Sabatier, MD, PhD ; Jean-Marc Simon, MD ; Marc
1
Benderitter, PhD ; and Radia Tamarat, PhD ; IRSN, Fontenay-aux-Roses, France ; CHU la Conception,
1
1
2
Marseille, France ; INSERM UMR-1076, Marseille, France ; and CHU La Pitié-Salpétrière, Paris, France
4
3
Microparticles (MPs) are membrane fragments with biological activities shed from damaged or
activated cells. MPs have been studied as biomarkers in several inflammatory diseases and as central
players in intercellular communication. In this study we investigated the potential use of MPs as
313 | P a g e
