3.1. Lamellipodia- and filopodia-driven cancer cell migration and
invasion
Lamellipodia are instrumental in mediating cancer cell invasion by
orchestrating the degradation of the ECM. Lamellipodia play a role in
forming invadopodia – specialized membrane structures that focus
proteolytic activity, facilitating localized ECM degradation [9].
This process is facilitated by the secretion of matrix
metalloproteinases (MMPs) and other proteolytic enzymes, enabling cancer
cells to breach physical barriers and invade surrounding tissues
[27]. The dynamic protrusions of lamellipodia create focal points
for the assembly of integrins, transmembrane receptors that connect the
cell to the ECM, fostering adhesion and promoting localized matrix
degradation [28,29]. In aggressive cancers, elevated expression of
MMPs in lamellipodia correlates with increased invasive potential. The
spatiotemporal regulation of ECM degradation by lamellipodia is critical
for tumor progression, allowing cancer cells to navigate through the
intricate matrix and invade neighboring tissues [30]. Additionally,
lamellipodia extend beyond their role in ECM degradation to facilitate
dynamic interactions with neighboring cells. Adhesion structures formed
by lamellipodia, such as focal adhesions, not only promote stable
attachments to the ECM but also enable communication between cancer
cells and surrounding stromal or immune cells [31]. This
intercellular crosstalk influences collective migration, allowing groups
of cancer cells to coordinate their invasive behavior [9]. Through
these interactions, lamellipodia contribute to the creation of a
permissive microenvironment that supports invasion and further
potentiates metastasis.
Filopodia, with their slender and elongated morphology, serve as sensory
extensions that guide cancer cells through the complex terrain of the
tumor microenvironment. Rich in receptors and adhesion molecules,
filopodia sense and respond to chemotactic gradients, allowing cancer
cells to navigate toward specific regions within the tumor. Through
dynamic probing and sensing, filopodia facilitate the recognition of
guidance cues, such as growth factors and chemokines, directing cancer
cells towards blood vessels or areas of increased stromal support. This
guidance is critical for the spatial organization of cancer cells within
the tumor, influencing invasion patterns and ultimately shaping the
metastatic potential of the cancer [25,26]. Filopodia play a crucial
role in the metastatic cascade, particularly during extravasation, where
cancer cells exit the bloodstream and invade distant tissues [18].
As cancer cells intravasate into the bloodstream, filopodia aid in their
interaction with endothelial cells, facilitating the adhesion to and
transmigration through the vascular endothelium [32]. Once in the
extravascular space, filopodia continue to contribute to metastasis by
guiding cancer cells through the foreign microenvironment. The ability
of filopodia to establish contacts with neighboring cells, including
stromal cells and other cancer cells, enhances their invasive potential.
Filopodia-driven invasion is thus a key determinant in the establishment
of secondary tumor foci, shaping the metastatic spread of cancer cells
[9].