Speech Title: Blood shear stress selects circulating tumor cells with metastatic advantages
INTRODUCTION: Metastasis is a multi-step process, including
detachment of cancer cells from primary and/or
metastatic lesions, intravasation, survival in
circulation, extravasation into distant organs,
and formation of metastatic tumors, which
accounts for over 90% of cancer-related
deaths 1 . During hematogenous metastasis,
survival of tumor cells in blood circulation is
one critical step. The presence and frequency of
circulating tumor cells (CTCs) are correlated
with poor prognosis in many cancer types.
Although a primary tumor releases thousands of
cancer cells every day into the circulation, less
than 0.01% of CTCs eventually grow into
metastatic tumors and most patients develop
very few metastases 1 , suggesting that metastasis
is highly inefficient. In particular, the half-life
of CTCs in circulation is limited and the
majority die within 24 hr. Therefore, survival of
CTCs in blood circulation is one major rate-
limiting step during metastasis. Although its
influence on CTC biology has been extensively
studied, the roles of blood shear flow in
metastatic potential of CTCs is unclear. In
particular, whether blood circulation selects a
minor subpopulation of CTCs with metastatic
advantages remains elusive.
METHODS: In this study, human breast cancer cells with
differential metastatic potential are adopted.
The corresponding cancer stem cells (CSCs) are
selected by culturing cancer cells in 3D soft
fibrin gels as demonstrated by our previous
research 2,3 . These cancer cells and the derived
CSCs are used for circulation in a circulatory
microfluidic system under various shear
stresses and circulation times. The viability of
these treated and non-treated cells is examined
by MTT. The migratory and invasive abilities
of both cells are measured by wound healing
analysis and transwell assay, respectively. To
explore the underlying mechanisms, the genes
related to metastasis and stemness are
quantified.
RESULTS AND DISCUSSION: Our data show that breast cancer cells with
high metastatic potential show higher survival
rate than cells with weak metastatic ability in
blood shear flow. Highly metastatic CSCs
selected by fibrin gels survive better in the
circulation than non-selected cancer cells.
These data suggest that metastatic CTCs have
the ability to survive blood circulation, which is
necessary for the subsequent extravasation and
the development of metastases. Moreover, cell
viability is related to the magnitude of shear
stress and circulation time. Importantly, those
survived cancer cells after blood circulation
exhibit enhanced migration and invasion
abilities, which are supported by the
upregulation of the genes related to metastasis
and stemness.
These data suggest that blood shear stress
not only eliminates CTCs with weak metastatic
ability but also selects a subpopulation with
metastatic advantages, highlighting the
importance of blood shear circulation in
metastasis.
ACKNOWLEDGEMENT: The study was financially supported by the
NSFC Grant (Ref. No. 11672255) and
the Internal Research Fund of the Hong Kong
Polytechnic University (Ref. No. 1-ZE4Q).