Introduction
Invadopodia are specialized, actin-rich structures that form on the surface of invasive cancer cells. These protrusions enable cancer cells to interact with and break down surrounding tissue barriers. Their primary purpose is to facilitate the movement of malignant cells through dense extracellular environments.
Cellular Composition and Formation
Invadopodia are dynamic structures with a core composed primarily of actin filaments, which are long, thin protein fibers providing structural support. The assembly of these actin filaments is orchestrated by proteins such as the Arp2/3 complex and N-WASP (neuronal Wiskott-Aldrich syndrome protein). Cortactin interacts with the actin cytoskeleton and helps organize the invadopodia structure.
Tks5 acts as a scaffold protein, bringing together molecules necessary for invadopodium formation and function. The lifecycle of an invadopodium involves several steps: initiation, extension, and eventual disassembly after its function is complete. Some invadopodia are short-lived and motile, while others are more stable and long-lived, persisting for several hours.
Mechanism of Tissue Invasion
Once formed, invadopodia actively degrade the extracellular matrix (ECM), the complex network of proteins and carbohydrates providing structural support to tissues. This degradation occurs through the localized secretion of specific enzymes called matrix metalloproteinases (MMPs). These MMPs, such as MMP-2 and MT1-MMP, function like molecular scissors, cutting through the protein components of the ECM.
The concentration of these enzymes at the invadopodium tip allows for focused and efficient ECM breakdown. This localized activity creates a pathway through dense tissue, enabling the cancer cell to move forward. This ECM remodeling prepares the environment for cellular movement and invasion. The ability to degrade and remodel the ECM is a direct consequence of invadopodia activity.
Role in Cancer Metastasis
Metastasis describes the spread of cancer cells from their original site to distant parts of the body, often forming new tumors. This process is the primary cause of death in cancer patients. Invadopodia play a role in several stages of this cascade. Their ability to degrade the extracellular matrix allows cancer cells to breach the basement membrane, a dense layer of ECM surrounding tissues, which is a necessary first step for escaping the primary tumor.
Following initial escape, invadopodia assist cancer cells in entering blood or lymphatic vessels, a process known as intravasation. Once within the circulatory system, these cells can travel to distant organs. Upon reaching a new site, invadopodia facilitate extravasation, the process of exiting vessels and invading new tissue to establish secondary tumors. The presence and activity of invadopodia are linked to the metastatic potential of various cancer types, including breast, colorectal, and bladder cancers.
Distinguishing from Podosomes
Invadopodia share some similarities with podosomes, another type of actin-rich protrusion, but differ in cellular context and function. Podosomes are found in normal cells, such as macrophages and osteoclasts, participating in physiological processes like immune surveillance and bone remodeling. Both structures possess an actin core and can degrade the extracellular matrix using similar enzymes.
Despite shared features, distinctions exist. Invadopodia are found in invasive cancer cells, while podosomes are part of normal cellular functions. Invadopodia are fewer in number per cell, ranging from one to ten, and have a longer lifetime, sometimes persisting for over eight hours. Podosomes are numerous and short-lived, lasting only a few minutes. This increased stability and focused degradation capacity of invadopodia contribute to their role in pathological tissue invasion.