Page 254 - 2014 Printable Abstract Book
P. 254
an important influencing factor in many others. Thus, an assessment of the effects of heavy ion radiation
on endothelial barrier function would be useful for estimating the risks of space travel. This study was
aimed at understanding the effects of high LET (1 GeV) Fe ions and is the first investigation of the effects
of charged particles on the function of the human endothelial barrier. We used a set of established and
novel endpoints to assess barrier function after exposure. These include, trans-endothelial electrical
resistance (TEER), morphological effects, localization of adhesion and cell junction proteins (in 2D
monolayers and in 3-D tissue models), and permeability of molecules through the endothelial barrier. A
dose of 50 cGy was sufficient to cause a progressive reduction in TEER measurements that were significant
48 hours after exposure. Concurrently, there were morphological changes and a 14% loss of cells from
monolayers. Gaps also appeared in the normally continuous cell-border localization of the tight junction
protein - ZO-1 but not the cell adhesion molecule PECAM-1 in both monolayers and in 3D vessel models.
Disruption of barrier function was confirmed by increase permeability to 3 kDa and 10 kDa dextran marker
molecules. A dose of 25 cGy caused no detectible change in cell number, morphology, or TEER, but did
cause barrier disruption since there were gaps in the cell border localization of ZO-1 and an increased
permeability to 3 kDa dextran. Similar results were obtained with other species of heavy ion particles such
as Si and O ions. These results indicate that heavy ion particles are potent inhibitors of human endothelial
barrier function and represent a risk for degenerative diseases in the space environment.
(PS4-32) High polarity polyphenol fractions from brown algae target radiation-induced tumor invasion
1
and metastasis in therapy-resistant residual pancreatic cancer. Satish Kumar Ramraj, PhD ; Natarajan
1
1
1
2
Aravindan, PhD ; Mohan Natarajan, PhD ; Vijayabaskar Pandian, PhD ; Faizan H. Khan, PhD ; Terence S.
3
1
Herman, MD ; and Sheeja Aravindan, MPhil, Oklahoma University Health Sciences Centre, Oklahoma city,
1
2
OK ; University of Texas Health Sciences Center at San Antonio, San Antonio, TX ; and Peggy and Charles
Stephenson Cancer Center, Oklahoma city, OK
3
Pancreatic cancer is one of the most challenging human malignancies characterized by its
deceptive symptoms, high risk of local invasion, metastasis and recurrence. Particularly, therapy
surviving tumor cells play a key role in tumor relapse, recurrence and metastasis. Recently we have
shown that polarity based fractions of seaweed polyphenols exert anti-pancreatic cancer potentials.
Enduring further, herein we investigated their potentials on the regulation of radiation orchestrated
tumor invasion and metastasis. Human pancreatic cancer cells (Panc1, Panc 3.27, BxPC3 and MiaPaCa-2)
exposed to radiation (2 Gy) with or without antioxidant and anti-tumorigenic polyphenol fractions from
Spatoglossum asperum (Drug 1, D1), Padina tetrastromatica (Drug 2, D2) and Hormophysa triquerta
(Drug 3, D3) were assessed for transcriptional regulation of human tumor invasion and metastasis
transcriptomes (QPCR profiling) of 93 molecules. Subsequently, we investigated the alterations in CREB,
N-cadherin, MMP-9 and pEGFR in clinical radiotherapy (FIR, 2Gy/D x 5D) surviving residual human
pancreatic cancer xenografts in athymic nude mice utilizing tissue microarray construction coupled with
automated IHC. Radiation significantly induced 36, 53, 29 and 42 stem cell related molecules in Panc1,
Panc 3.27, BxPC3 and MiaPaCa-2, respectively. Seaweed polyphenols completely suppressed the
radiation orchestrated (D1-24, D2-17, D3-15 of 36 IR-induced genes in Panc-1 cells; D1-44, D2-44, D3-44
of 53 IR-induced genes in Panc-3.27 cells; D1-13, D2-13, D3-12 of 29 IR-induced genes in BxPC3 cells; D1-
26, D2-29, D3-26 of 42 IR-induced genes in MiaPaCa-2 cells) tumor invasion and metastasis molecules.
TMA-IHC analysis further showed significant suppression in the cellular localization and expression of
CREB, N-cadherin, MMP-9 and pEGFR in residual pancreatic cancer with D3 treatment. These data
252 | P a g e
on endothelial barrier function would be useful for estimating the risks of space travel. This study was
aimed at understanding the effects of high LET (1 GeV) Fe ions and is the first investigation of the effects
of charged particles on the function of the human endothelial barrier. We used a set of established and
novel endpoints to assess barrier function after exposure. These include, trans-endothelial electrical
resistance (TEER), morphological effects, localization of adhesion and cell junction proteins (in 2D
monolayers and in 3-D tissue models), and permeability of molecules through the endothelial barrier. A
dose of 50 cGy was sufficient to cause a progressive reduction in TEER measurements that were significant
48 hours after exposure. Concurrently, there were morphological changes and a 14% loss of cells from
monolayers. Gaps also appeared in the normally continuous cell-border localization of the tight junction
protein - ZO-1 but not the cell adhesion molecule PECAM-1 in both monolayers and in 3D vessel models.
Disruption of barrier function was confirmed by increase permeability to 3 kDa and 10 kDa dextran marker
molecules. A dose of 25 cGy caused no detectible change in cell number, morphology, or TEER, but did
cause barrier disruption since there were gaps in the cell border localization of ZO-1 and an increased
permeability to 3 kDa dextran. Similar results were obtained with other species of heavy ion particles such
as Si and O ions. These results indicate that heavy ion particles are potent inhibitors of human endothelial
barrier function and represent a risk for degenerative diseases in the space environment.
(PS4-32) High polarity polyphenol fractions from brown algae target radiation-induced tumor invasion
1
and metastasis in therapy-resistant residual pancreatic cancer. Satish Kumar Ramraj, PhD ; Natarajan
1
1
1
2
Aravindan, PhD ; Mohan Natarajan, PhD ; Vijayabaskar Pandian, PhD ; Faizan H. Khan, PhD ; Terence S.
3
1
Herman, MD ; and Sheeja Aravindan, MPhil, Oklahoma University Health Sciences Centre, Oklahoma city,
1
2
OK ; University of Texas Health Sciences Center at San Antonio, San Antonio, TX ; and Peggy and Charles
Stephenson Cancer Center, Oklahoma city, OK
3
Pancreatic cancer is one of the most challenging human malignancies characterized by its
deceptive symptoms, high risk of local invasion, metastasis and recurrence. Particularly, therapy
surviving tumor cells play a key role in tumor relapse, recurrence and metastasis. Recently we have
shown that polarity based fractions of seaweed polyphenols exert anti-pancreatic cancer potentials.
Enduring further, herein we investigated their potentials on the regulation of radiation orchestrated
tumor invasion and metastasis. Human pancreatic cancer cells (Panc1, Panc 3.27, BxPC3 and MiaPaCa-2)
exposed to radiation (2 Gy) with or without antioxidant and anti-tumorigenic polyphenol fractions from
Spatoglossum asperum (Drug 1, D1), Padina tetrastromatica (Drug 2, D2) and Hormophysa triquerta
(Drug 3, D3) were assessed for transcriptional regulation of human tumor invasion and metastasis
transcriptomes (QPCR profiling) of 93 molecules. Subsequently, we investigated the alterations in CREB,
N-cadherin, MMP-9 and pEGFR in clinical radiotherapy (FIR, 2Gy/D x 5D) surviving residual human
pancreatic cancer xenografts in athymic nude mice utilizing tissue microarray construction coupled with
automated IHC. Radiation significantly induced 36, 53, 29 and 42 stem cell related molecules in Panc1,
Panc 3.27, BxPC3 and MiaPaCa-2, respectively. Seaweed polyphenols completely suppressed the
radiation orchestrated (D1-24, D2-17, D3-15 of 36 IR-induced genes in Panc-1 cells; D1-44, D2-44, D3-44
of 53 IR-induced genes in Panc-3.27 cells; D1-13, D2-13, D3-12 of 29 IR-induced genes in BxPC3 cells; D1-
26, D2-29, D3-26 of 42 IR-induced genes in MiaPaCa-2 cells) tumor invasion and metastasis molecules.
TMA-IHC analysis further showed significant suppression in the cellular localization and expression of
CREB, N-cadherin, MMP-9 and pEGFR in residual pancreatic cancer with D3 treatment. These data
252 | P a g e
