Increased, Motility leads to Increased, Invasion

Biological plausibility (Egebald, Hodgkinson, Agarwal, Saha, Friedel)

Extracellular Matrix (ECM) Interaction: Cancer cells with enhanced motility often exhibit changes in surface receptors and cytoskeletal dynamics, allowing them to adhere to and move through the ECM more effectively. This is crucial for breaching physical barriers and invading neighboring tissues.

Proteolytic Enzyme Secretion: Highly motile cancer cells often secrete proteolytic enzymes, such as matrix metalloproteinases (MMPs), that break down ECM proteins. This proteolytic activity facilitates the remodeling of the ECM, enabling cancer cells to invade surrounding tissues and enter blood or lymphatic vessels.

Dynamic Cell-Cell and Cell-ECM Interactions: Increased cell motility allows cancer cells to form and disassemble focal adhesions with neighboring cells and the ECM. This dynamic interaction promotes efficient migration and invasion, enabling cancer cells to adapt to the changing microenvironment during invasion.

Chemotaxis and Chemoattractants: Cancer cells with increased motility are more responsive to chemoattractants, signaling molecules that guide cell movement. Chemotaxis allows cancer cells to navigate towards blood vessels, lymphatic vessels, or specific tissues, facilitating invasion into distant organs.

Formation of Cellular Protrusions: Highly motile cancer cells often extend dynamic protrusions like lamellipodia and filopodia. These structures increase the surface area of contact with the surrounding environment, allowing cancer cells to explore and invade tissues efficiently.

Adaptation to Microenvironmental Challenges: Increased motility enables cancer cells to navigate through physical barriers, adapt to varying oxygen levels, and respond to microenvironmental cues. This adaptability is crucial for successful invasion into different organ environments.

Involvement in Collective Migration: Collective migration, where multiple motile cells move as a coordinated front, enhances the invasive potential of a group of cancer cells. Increased motility of individual cells contributes to the overall success of collective invasion.

Survival and Escape from Immune Surveillance: Increased motility allows cancer cells to escape immune surveillance by quickly moving through tissues and avoiding immune responses. This is crucial for the survival of circulating tumor cells during metastasis.

Angiogenesis and Intravasation: Increased motility contributes to the ability of cancer cells to intravasate into vessels. It is also associated with angiogenesis, the formation of new blood vessels, providing a route for cancer cells to enter the bloodstream.

Empirical evidence supporting the association between increased cell motility and organ invasion comes from various experimental studies, both in vitro and in vivo. Here are examples of empirical evidence demonstrating how enhanced cell motility contributes to organ invasion:

• In Vitro Cell Migration and Invasion Assays (Transwell or Boyden chamber assays): Cells with increased motility demonstrate higher migration through porous membranes coated with extracellular matrix (ECM) components (Friedl, Yurchenco). In invasive assays, these cells penetrate ECM barriers more efficiently than less motile cells, providing direct evidence of a correlation between motility and invasion. In a wound healing assay, cancer cells with enhanced motility exhibit faster wound closure, indicating increased invasive potential (Agarwal)
• Three-Dimensional (3D) Invasion Models: Cells with enhanced motility exhibit increased invasion into 3D matrices. These models better represent the complexity of tissue architecture, highlighting the relevance of motility in navigating through a three-dimensional environment.
• In Vivo Orthotopic Xenograft Models: High motility correlates with increased invasion into surrounding tissues and metastasis to distant organs (wiseman, valastyan). Imaging techniques, such as bioluminescence or positron emission tomography (PET), allow tracking of tumor cells in vivo, providing evidence of invasion into organs.
• Intravital Imaging: Intravital imaging studies reveal that cells with increased motility exhibit enhanced invasion into organs. Researchers can directly observe the movement of cells within the complex microenvironment of living tissues.
• Genetic Manipulation of Cell Motility (e.g., overexpression or knockdown of motility-related genes) : Cells with increased motility, due to genetic modifications, consistently demonstrate higher invasive potential. Conversely, inhibiting motility-related genes results in decreased invasion.
• Pharmacological Modulation of Motility: Treatment with motility-inhibiting compounds results in reduced invasion both in vitro and in vivo. Conversely, stimulation of motility-related pathways increases invasive behavior.
• Correlation Studies in Patient Samples: Increased expression of motility-related markers in patient tumors correlates with a higher likelihood of organ invasion and metastasis. This clinical evidence supports the association between cell motility and invasive behavior. Moreover, patients with tumors exhibiting higher motility markers often have a poorer prognosis, increased likelihood of metastasis, and higher rates of organ invasion compared to those with less motile tumors (Gupta, Sahao).
• In Vitro Microfluidic Models: Cells with increased motility demonstrate enhanced invasion through microfluidic channels, simulating the conditions encountered in the circulatory system or within organs.

While there is substantial empirical evidence supporting the notion that increased cell motility contributes to increased organ invasion, it is important to acknowledge uncertainties and inconsistencies in the literature. These uncertainties stem from the complexity of biological systems, the heterogeneity of tumors, and variations in experimental methodologies. Here are some potential uncertainties and inconsistencies:

• Tumor Heterogeneity: Variability in motility within a tumor may lead to inconsistent observations, with some regions demonstrating enhanced invasion while others do not (Friedl, Valastyan).
• Context Dependency: The role of increased cell motility in invasion may vary depending on the tumor type, microenvironment, and organ of interest (Friedl, Valastyan). For example, breast and pancreatic cancers exhibit a strong dependence on motility for invasion, while gliomas (brain tumors) infiltrate surrounding tissues through a different mechanism known as amoeboid movement, potentially minimizing the role of classical motility (Friedl, Valastyan).
• In Vitro vs. In Vivo Discrepancies: Increased motility observed in cell culture may not translate to enhanced invasion in complex in vivo settings, possibly due to differences in the microenvironment and additional factors influencing invasion. For example, The ECM composition in model systems often doesn't fully capture the diverse components and architecture found in real tumors, potentially influencing cell motility and invasion differently (Hodgkinson).
• Divergent Experimental Models: Varied experimental models, including xenografts, organoids, and in vitro cultures, may produce different outcomes. For instance, Most preclinical models lack a functional immune system, neglecting the role of immune cells in either aiding or hindering invasion (Gentezl).
• Dynamic Tumor Microenvironment: The tumor microenvironment is dynamic, and factors such as hypoxia, inflammation, and immune responses can influence invasion. Interactions with the dynamic microenvironment may modulate the relationship between cell motility and invasion, introducing complexities and uncertainties.
• Adaptation and Compensation: Over time, compensatory mechanisms may mask the direct impact of increased motility on invasion, leading to inconsistencies in experimental outcomes.
• Genetic and Epigenetic Variations: The contribution of increased motility to invasion may be influenced by other genetic or epigenetic alterations, introducing variability in experimental outcomes.
• Timing of Measurements: Assessments conducted at different stages of tumor progression may yield varied results, and the temporal dynamics of increased motility and invasion need to be considered.
• Artifactual Observations: Inconsistencies may arise from variations in the accuracy and sensitivity of experimental methods used to assess motility and invasion.