The delicate balance and spatiotemporal regulation of Rho GTPase
activity determine the type and extent of protrusions formed, playing a
central role in the migratory and invasive behavior of cancer cells.
These GTPases activate downstream effectors such as Rho-associated
protein kinases (ROCK1/2) that facilitate the phosphorylation of myosin
light chains (MLC), leading to increased actomyosin contractility.
Simultaneously, LIM kinases (LIMK) phosphorylate cofilin (p-cofilin),
which prevents actin filament depolymerization, thus stabilizing the
cytoskeleton. Meanwhile, proteins like mDia2 and N-WASP, in conjunction
with the Arp2/3 complex, promote actin nucleation, a process fundamental
to the polymerization of actin filaments, giving rise to the dynamic
restructuring of the cytoskeleton. Concurrently, the cell coordinates
the trafficking and releasing of matrix metalloproteinases (MMPs) via
molecules such as IQGAP. MMPs are proteolytic enzymes that degrade
components of the extracellular matrix, clearing a path through the
tissue and enabling the invasive behavior of the tumor cell [49].
The proteins WASP and WASP-family Verprolin-homologous protein (WAVE),
integral to Rho GTPase signaling, are key regulators of the actin
cytoskeleton, playing crucial roles in the formation of lamellipodia and
filopodia. They are activated by Rho family GTPases, such as Rho, Rac1,
and Cdc42, leading to the formation of cellular protrusions essential
for cell motility. In cancer, this mechanism becomes pivotal, as the
dynamic rearrangement of the actin cytoskeleton facilitates invasive and
metastatic behaviors of tumor cells. These proteins serve as critical
activators of the actin cytoskeleton, which plays a central role in the
morphological and motile capabilities of cancer cells. The activation of
specific Rho GTPases - Rho, Rac1, and Cdc42 - by WASP and WAVE leads to
the formation of actin stress fibers, membrane ruffles, lamellipodia,
and filopodia. These actin structures are not merely components of
cellular architecture but are actively involved in the directional
motility of cancer cells, a key process in the invasion of surrounding
tissues and the progression to metastasis. The actin cytoskeleton’s
dynamic reorganization, facilitated by these proteins, enables cancer
cells to form cellular protrusions essential for their movement and
interaction with the extracellular matrix. This interaction is
particularly important for the cells’ ability to degrade barriers, a
prerequisite for invasive behavior. Moreover, these structures enable
the cells to navigate complex extracellular environments, aiding in
their metastatic spread. Furthermore, by influencing the actin dynamics
and cell motility, these proteins emerge as potential targets for
therapeutic interventions aimed at mitigating cancer metastasis
[50,51].
Colorectal cancer, the third leading cause of cancer-related deaths
globally, has been linked to WAVE2 expression. Studies indicate WAVE2’s
association with liver metastasis, disease progression, and the
activation of TGF-β1 and YAP1 signaling pathways in colorectal cancer.
WAVE2’s role is critical in colorectal liver metastasis, particularly
through its regulation by TGF-β1 in the cancer immune microenvironment.
In cervical cancer, which predominantly affects women aged 35-44,
overexpression of SH3BP1 has been found to increase Rac1 and WAVE2
activity, enhancing invasion, migration, and chemoresistance. WAVE2 has
also been implicated in the invasiveness and motility of pancreatic
cancer cells. It is shown that WAVE2 interacts with alpha-actinin 4
(ACTN4), affecting cell movement and invasiveness. Prostate cancer
research indicates the involvement of WAVE2 in cell invasion and
metastasis, particularly through its interaction with PIP3 and
Rac1-induced actin reorganization. WAVE2 is also significant in breast
cancer, the most common cancer among women worldwide. It contributes to
the formation of lamellipodial protrusions in cancer cells and is
associated with aggressive cancer types like triple-negative breast
cancer (TNBC). The binding of WAVE2 to the Arp2/3 complex plays a
crucial role in breast cancer cell migration and invasion, with
implications for potential therapeutic targets [51].
Integrins, transmembrane receptors that link the ECM to the actin
cytoskeleton, also play a pivotal role in regulating lamellipodia and
filopodia dynamics [29,52]. Integrin engagement with the ECM
initiates signaling cascades that influence focal adhesion formation and
cytoskeletal rearrangements. Integrins activate focal adhesion kinase
(FAK) and Src kinases, initiating downstream signaling events that
regulate the activity of Rho GTPases. Focal adhesions serve as anchoring
points for actin filaments and contribute to the stability of
lamellipodia and filopodia [53]. The turnover of these focal
adhesions is essential for dynamic cell movement. The interplay between
integrins, focal adhesion signaling, and Rho GTPases coordinates the
adhesive and protrusive forces required for effective cell migration and
invasion in the tumor microenvironment [16].