Page 12 - 2014 Printable Abstract Book
P. 12
average size of 250 nm. The activity appeared to be associated with the vesicle surface since physical
disruption of the SV and preparation of SV-CM did not release activity, and unlike soluble factors, SV
expressed activity in a 2-layer culture system only when added to the layer containing target progenitor
cells. We subsequently reported that (1) activity on SV is antigenically related to purified BPA prepared
from the PM, and released in an energy-dependent, directed fashion, (3) fluidization of the PM and its
derivative SV increases membrane width determined by x-ray diffraction and induces the expression of a
negative regulator of erythropoiesis, (4) structurally distinct PM regions give rise to SV, and (5) other
bioactive growth regulators are exfoliated on SV, including M-CSF, Flt3/Flk2, Fas and Fas ligand. Additional
growth and immune regulators are enriched in SV/ectosomes (including TGF, VEGF, FGF2, IL-1 beta, TRAIL
and FcR) and ectosomes (such as cytokines, MHC-I and -II, integrins and ICAM-1). As the number of
publications on MV has increased exponentially over the past decade, multiple investigators have
reported that MV mediate cell-cell communication in diverse biosystems, including coagulation (via
platelet MV), inflammation (via neutrophil and fibroblast MV), immunity (via dendritic cell and
lymphocyte MV) and tumor cell progression (via cancer cell and macrophage MV). IR induces structural
alterations in the PM, including induction of hydroperoxides and their breakdown products. These
changes are associated with a liquid crystal-to-gel phase transition, resulting in enhanced ordering of
lipids, increased PM microviscosity, decreased fluidity and decreased PM width, and ultimately,
facilitating the formation of membrane buds. We noted that cumulative release of SV from SW620, CHO
and T-cells is increased within 4 hr following exposure to 0.5 Gy with no change in viability, and that IR
induces dose-dependent up-regulation of bioactive Fas and Fas ligand on both the PM and SV, providing
a potential mechanism for abscopal and bystander effects of radiation. The fate and mechanism of
transfer of segregated growth and death signals on SV to and from stem/progenitor cells is under
investigation. Today, IR-induced miRNA profiles on circulating and excreted MV are being determined in
an effort to develop new biomarkers of exposure. Standardized MV purification methods, confirmation of
vesicle subtype and exclusion of apoptosis-related vesiculation will be needed, as the biological basis and
specificity of such potential biomarkers are deciphered. Moreover, future exploitation of the capacity of
MV to express cytokines, reduce tissue injury, modulate immunity and transfer resistance may lead to the
discovery of novel radiomitigators.
LESSONS FROM CANCER GENOME SEQUENCING
(P003) Lessons from Cancer Genome Sequencing. Kenneth W. Kinzler Johns Hopkins University,
Baltimore, MD
The advent of massively parallel sequencing has revolutionized the genetic analyses of cancer and
there have now been well over 100 genome wide studies of human cancer. The implications of these
studies for the biology and clinical management of cancer will be discussed.
10 | P a g e
disruption of the SV and preparation of SV-CM did not release activity, and unlike soluble factors, SV
expressed activity in a 2-layer culture system only when added to the layer containing target progenitor
cells. We subsequently reported that (1) activity on SV is antigenically related to purified BPA prepared
from the PM, and released in an energy-dependent, directed fashion, (3) fluidization of the PM and its
derivative SV increases membrane width determined by x-ray diffraction and induces the expression of a
negative regulator of erythropoiesis, (4) structurally distinct PM regions give rise to SV, and (5) other
bioactive growth regulators are exfoliated on SV, including M-CSF, Flt3/Flk2, Fas and Fas ligand. Additional
growth and immune regulators are enriched in SV/ectosomes (including TGF, VEGF, FGF2, IL-1 beta, TRAIL
and FcR) and ectosomes (such as cytokines, MHC-I and -II, integrins and ICAM-1). As the number of
publications on MV has increased exponentially over the past decade, multiple investigators have
reported that MV mediate cell-cell communication in diverse biosystems, including coagulation (via
platelet MV), inflammation (via neutrophil and fibroblast MV), immunity (via dendritic cell and
lymphocyte MV) and tumor cell progression (via cancer cell and macrophage MV). IR induces structural
alterations in the PM, including induction of hydroperoxides and their breakdown products. These
changes are associated with a liquid crystal-to-gel phase transition, resulting in enhanced ordering of
lipids, increased PM microviscosity, decreased fluidity and decreased PM width, and ultimately,
facilitating the formation of membrane buds. We noted that cumulative release of SV from SW620, CHO
and T-cells is increased within 4 hr following exposure to 0.5 Gy with no change in viability, and that IR
induces dose-dependent up-regulation of bioactive Fas and Fas ligand on both the PM and SV, providing
a potential mechanism for abscopal and bystander effects of radiation. The fate and mechanism of
transfer of segregated growth and death signals on SV to and from stem/progenitor cells is under
investigation. Today, IR-induced miRNA profiles on circulating and excreted MV are being determined in
an effort to develop new biomarkers of exposure. Standardized MV purification methods, confirmation of
vesicle subtype and exclusion of apoptosis-related vesiculation will be needed, as the biological basis and
specificity of such potential biomarkers are deciphered. Moreover, future exploitation of the capacity of
MV to express cytokines, reduce tissue injury, modulate immunity and transfer resistance may lead to the
discovery of novel radiomitigators.
LESSONS FROM CANCER GENOME SEQUENCING
(P003) Lessons from Cancer Genome Sequencing. Kenneth W. Kinzler Johns Hopkins University,
Baltimore, MD
The advent of massively parallel sequencing has revolutionized the genetic analyses of cancer and
there have now been well over 100 genome wide studies of human cancer. The implications of these
studies for the biology and clinical management of cancer will be discussed.
10 | P a g e
