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Hu et al. J Cancer Metastasis Treat 2018;4:39 I http://dx.doi.org/10.20517/2394-4722.2018.08 Page 3 of 8

THE DETACHMENT OF CANCER CELLS FROM THE PRIMARY TUMOR
The development of PD is initiated by penetration of cancer cells through the gastric wall. In this step, cancer
cells must have the ability to migrate and invade for successful detachment from the primary tumor and for
gaining access to the peritoneal cavity. E-cadherin is a calcium-dependent cell - cell adhesion molecule that
plays a crucial role in establishing the epithelial architecture and maintaining cell polarity. Dysregulation
of E-cadherin contributes to tumor invasion by promoting cell motility [10,11] , resulting in PD. Moreover,
E-cadherin and the cadherin - catenin complex may promote invasion and migration by modulating various
[12]
signaling pathways in epithelial cells, including Wnt signaling , Rho GTPase [13,14] , and NF-κB pathways [15,16] ,
as well as epithelial-mesenchymal transition (EMT) [13,17] .

The activation of Rho GTPases (RhoA, cdc42, Rac) also drives cancer cell motility and invasion by
promoting actin cytoskeleton reorganization [18-20] . The formation of lamellipodia and filopodia (resulting
in actin cytoskeleton reorganization), which are regulated by Rac and cdc42, respectively, contributes to
cancer cell motility . In a previous study, ADP-ribosylation factor-like 4C (ARL4C), a downstream factor
[18]
of EGF signaling and Wnt signaling, was reported to promote cell motility by activating Rho GTPases .
[21]
We recently found that ARL4C is associated with PD in GC, possibly by promoting the invasive capacity of
cancer cells via activation of both EMT and actin cytoskeleton reorganization . ARL4C is proposed to be a
[22]
novel biomarker and potential therapeutic target for GC patients with PD.
In the process of cancer cell invasion, overexpression of matrix metalloproteinases (MMPs) is required for
degradation of the extracellular matrix (ECM) [23,24] . High expression of MMP-7 is a reported risk factor
for PD in GC , and MMP-2 and MMP-9 are also associated with the invasive capacity of gastrointestinal
[25]
cancer cells [24,26,27] . Furthermore, MMP-14 can activate MMP-2 in addition to degradation of ECM .
[28]
EMT is an essential phenotypic conversion mechanism that has been implicated in the initiation of
metastasis and tumor progression in many types of cancers . During EMT, epithelial cells exhibit enhanced
[29]
motility and invasiveness , low expression of E-cadherin, high expression of vimentin, a spindle shape, and
[30]
reduced adhesion. The major ligands involved in EMT are EGF, TGFβ, Wnt, Notch, and integrin. The major
transcription factors that induce EMT via downregulation of E-cadherin expression are Twist, Snail,
[13]
Slug, Zeb1, and Zeb2 [31-33] . We focused on the influence of EMT on PD and found that discoidin domain-
containing receptor 2 promoted PD in GC via induction of EMT .
[34]

CELL SURVIVAL IN THE MICROENVIRONMENT OF THE PERITONEAL CAVITY
The microenvironment of the free abdominal space is hypoxic and deficient in glucose . The cancer cells,
[35]
which are seeded in the peritoneal cavity, must survive, proliferate, and migrate in this environment. Cell
adhesion to appropriate ECM components with integrin and cadherin is essential for cell survival, and
loss of this adhesion induces cell death, which has been termed “anoikis”. Therefore, anoikis resistance is
required for cells surviving in the peritoneal cavity and anchorage-independent growth .
[36]
HIF1α is reportedly involved in PD in GC, colorectal cancer, and pancreatic cancer [35,37] . HIF1α is induced
by hypoxia and functions as a master regulator of cellular and systemic homeostatic responses to hypoxia
by activating the transcription of many genes, including those involved in glucose metabolism and other
adaptations to hypoxia [38-40] . Interestingly, HIF1α induces EMT by activating the transcription of genes in
the LOX family . EMT contributes to not only migration and invasion but also anoikis resistance in cancer
[41]
cells [42,43] . HIF1α also induces angiopoietin-like-4 (ANGPTL4), a secreted protein essential for tumor growth
and resistance to anoikis in GC cells .
[44]

Cancer cells develop anoikis resistance via several mechanisms, including changes in integrin repertoire
expression, induction of EMT, oncogene activation, and adaption of their metabolism [45-47] . In gastrointestinal