1. Introduction
Cancer cell migration is a critical factor in cancer progression,
facilitating the invasion and dissemination of cancer cells from primary
tumors to establish metastases in distant organs. This process is
complex and involves the integration of signaling pathways that regulate
cell adhesion, cytoskeleton reorganization, and interactions with the
tumor microenvironment [1–3]. Among others, collective movement,
mesenchymal migration, and amoeboid migration are crucial aspects of
cancer migration, each characterized by distinct mechanisms and
implications in the progression of cancer. Collective cell movement
involves the coordinated migration of groups of cancer cells. it is
characterized by cells moving as sheets, strands, clusters, or ducts,
and is regulated by cadherin-based junctions maintaining supracellular
properties like collective polarization and force generation [4]. It
has been seen in various cancers and relies on cell-cell adhesion
mechanisms to maintain the integrity and directionality of the group.
Studies have shown that beta1 integrins play a critical role in the
invasive migration of multicellular clusters, such as in primary
melanoma explants. Disruption of beta1-integrin function can lead to the
detachment of individual cells and switch to amoeboid migration,
highlighting the plasticity in tumor cell migration strategies [5].
Whilst, mesenchymal migration enables cancer cells to move individually.
It is characterized by the formation of focal adhesions and the
elongation of the cell body. The transition from mesenchymal to amoeboid
migration can be induced by changes in the microenvironment, such as
confinement and low adhesion, allowing mesenchymal cells to switch to a
fast amoeboid phenotype [6]. Amoeboid migration is characterized by
high plasticity, allowing cancer cells to move independently of
adhesions, often through squeezing and deforming their cell body. This
mode can be induced under certain conditions, such as hypoxia, which
triggers a collective-to-amoeboid transition promoting the dissemination
of amoeboid-moving single cells from collective invasion strands. This
process involves hypoxia-inducible factors (HIF-1) and demonstrates the
adaptive capability of cancer cells to environmental challenges [7].
Cellular dynamics in cancer progression have become a focal point of
research, unveiling the intricate roles played by subcellular structures
like lamellipodia and filopodia. Lamellipodia, broad, sheet-like
protrusions, and filopodia, slender, finger-like extensions, are dynamic
membrane structures crucial for cellular movement and interaction within
the complex tumor microenvironment. They are dynamic extensions
emanating from the leading edge of migrating cells, orchestrating
directed cell movement through the intricate interplay of the actin
cytoskeleton. Lamellipodia, characterized by a broad, flattened
morphology, drive cell migration by promoting adhesion to the
extracellular matrix (ECM) and facilitating the establishment of focal
contacts. On the other hand, filopodia, with their slender, finger-like
appearance, are involved in cellular probing, sensing the
microenvironment, and guiding directional movement [8,9]. Comprising
a dense network of actin filaments, lamellipodia and filopodia exhibit
distinct molecular and structural features. Lamellipodia are enriched
with branched actin networks, largely regulated by the Actin-Related
Protein 2/3 (Arp2/3) complex and the Wiskott-Aldrich Syndrome Protein
(WASP) [8,10,11]. In contrast, filopodia exhibit bundled actin
filaments regulated by proteins like fascin and the
Enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) family members
[9,12–14]. These structural variances contribute to their
specialized functions in cellular motility and invasion.
The relevance of lamellipodia and filopodia in cancer progression lies
in their pivotal roles in the tumor invasion and metastatic cascade
[9]. Cancer cells exploit these structures to navigate through the
intricate matrix of the tumor microenvironment, invade surrounding
tissues, and disseminate to distant sites [15]. Lamellipodia-driven
migration facilitates the invasion of cancer cells by promoting ECM
degradation and enabling efficient interaction with neighboring cells
[16,17]. Moreover, filopodia play a crucial role in guiding cancer
cells through the complex extracellular milieu, aiding in processes such
as intravasation and extravasation during metastasis [18]. Beyond
their physical contributions to invasion, these membrane protrusions
actively participate in signal transduction pathways. They respond to
extracellular cues, translating environmental signals into intracellular
responses that modulate cellular behaviors. The dysregulation of these
signaling processes contributes to aberrant cancer cell motility and
invasiveness, making lamellipodia and filopodia promising targets for
therapeutic intervention [10,19,20].
This review aims to provide a comprehensive synthesis of current
knowledge regarding the structural and functional intricacies of
lamellipodia and filopodia in the context of cancer progression. By
critically evaluating existing literature and integrating findings from
diverse studies, we seek to offer a holistic understanding of how these
protrusions contribute to cancer cell invasion and metastasis.
Furthermore, this review serves as a platform for discussing the
regulatory mechanisms governing lamellipodia and filopodia dynamics in
cancer cells. Insights into the signaling pathways and key molecular
players involved will be dissected, providing a roadmap for potential
therapeutic interventions. Beyond elucidating their roles in cancer
progression, this review will explore the clinical implications of
lamellipodia and filopodia, considering their potential as diagnostic
and prognostic markers.