The influence of radiation induced TGF on the …debreastcancer.org/pdf/DBCC_Update_Poster.pdfHelen...
Transcript of The influence of radiation induced TGF on the …debreastcancer.org/pdf/DBCC_Update_Poster.pdfHelen...
Sangjucta Barkataki; Lisanne Wenting; Kenneth L. van Golen, PhD;
Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA
Abstract Cell lines in the study
Background
IBC and melanoma.
Role of TGFβ in the etiology of melanoma cutaneous metastasis
(Rufli 1995; Mauviel 2013).
TGFβ signalling switches breast cancer cells from cohesive to
single cell motility – EriK Sahai (2009)
Steven van Laere (2014) – circulating TGFb in patients. Very
low TGFb in IBC patients, TGFβ signal very poor in tumors.
Van Golen’s lab – TGFβ response, size of emboli and cluster
type to single cell invasion.
Skin metastasis in IBC and melanoma (Fidler 1990; Darvishian
2011; Garbe 2004).
Dr. van Golen – melanoma cells also forms emboli.
In melanoma -when TGFβ is increased in the stroma due to
radiation, there is single cell invasion (Rufli 1995; Mauviel 2013).
Breast cancer – most prevalent, 60% of cutaneous metastases
cases (Rosen2003).
Skin metastases representation of systemic spread of the
disease.
IBC cutaneous metastasis - chest wall recurrences.
Inflammatory Breast Cancer (IBC) is the deadliest form of epithelial
breast cancer, accounting for ~10% of breast cancer deaths in the
United States. A hallmark of IBC is the formation intralymphatic
emboli that are known to be chemotherapy and radiation resistant
and contribute to rapid metastasis. This form of breast cancer
progresses very quickly, expressing aggressive behavior. IBC and
melanoma share a number of similarities in disease presentation
and progression. Both spread via dermal lymphatics, form
intralymphatic emboli and have a propensity to form cutaneous
metastases. Melanoma can also present as “inflammatory
melanoma”, which resembles IBC phenotypically. Thus, new leads
for studying cutaneous metastasis can be gathered from the
melanoma literature. Studies demonstrate a role for transforming
growth factor beta (TGFβ) in the etiology of melanoma cutaneous
metastasis. TGFβ promotes tumor cell invasion and its expression
can be induced in the stroma by radiation treatment. Recently, our
lab has demonstrated low expression of TGFβ in IBC patients,
which we believe promotes cohesive invasion of IBC cells.
Stimulation of IBC cells with 2ng/ml of TGFβ causes altered tumor
cell behavior such as stimulating single cell invasion. The invasion
of KPL4, SUM149 and MDA-MB231 cell lines were significantly
higher in TGFβ stimulated cells compared to non-stimulated cells.
As in melanoma cells we hypothesize that radiation enhanced
local TGFβ production in the stroma. We radiated normal human
epidermal fibroblasts cells with 0gy, 0.5gy, 1.0gy, 2.5gy and 5.0gy
intensity and observed that the invasion was significantly higher in
1.0gy, 2.5gy and 5.0gy. Results shows presence of TGFβR2 in IBC
cells as well as TGFβ2 expressions by irradiated fibroblasts. Our
prediction is that the increase in the invasion of IBC cells is
because of TGFβ, which alters the cohesive nature of IBC cells,
and enhance single cell invasion. Moreover, radiation increases
TGFβ levels in the stroma, which is responsible for rapid
metastasis of IBC cells to the skin.
The influence of radiation induced TGFβ on the development of inflammatory breast cancer’s (IBC) cutaneous metastases
Preliminary data
Results: Fractionated dose
Results: Radiation therapy results in
IBC invasion
Results: TGFβ inhibitors SB431542
and LY2109761
Results: Gene expression in
fibroblasts and IBC cells
SUM149
AcknowledgementWe are sincerely grateful to Inflammatory Breast
Cancer Network Foundation for the funding for the
project.
Thank you DBCC for the recognition and the travel
award.
This study is dedicated to the memory of Kathleen
Strosser, who was an inspiration and enormous
supporter of our work
Conclusions
Results: Immunofluorescence and
Flow Cytometer