Encyclopedia of Cancer, 2015
Infiltration; tumor cell invasion
Is a process in malignant cells consisting of penetration of and movement through surrounding tissues.
Following an initial period of cell proliferation at the tissue site of origin, malignant cells acquire the capacity to undergo invasion of the surrounding tissues. Some malignant neoplasms undergo extensive local invasion without metastasizing, but invasion is a prerequisite for the development of metastasis.
Although the process is not the same for all types of malignancies, the invasion of epithelialderived malignant cells (the most common type) involves the following steps (Fig. 1):
- Detachment from adjacent cells and underlying basement membrane
- Disruption and degradation of surrounding matrix
- Adhesion to surrounding matrix components
- Migration through the adjacent tissue
Epithelial cells are normally connected to each other by means of tight junctions, adherens junctions, and desmosomes. Transmembrane adhesion proteins, particularly the cadherin family of membrane glycoproteins, are important components of these cell junctions. Epithelial cells are also adherent to an underlying basement membrane by means of focal adhesions and hemidesmosomes, and integrins are important components of these cell-matrix adhesion complexes. The detachment of tumor cells from adjacent cells and the underlying basement membrane involves disruption of such cell-cell and cell-matrix adhesion structures.
In order to invade the surrounding connective tissue, tumor cells must penetrate the underlying basement membrane. Tumor cells induce secretion of a variety of proteases that become activated and cleave basement membrane proteins, such as collagen IV and laminin. Disruption of the basement membrane provides the malignant cells access to the surrounding connective tissue. Further degradation of connective tissue components by proteases and other enzymes provides a pathway that allows the tumor cells to traverse the connective tissue matrix.
Fig. 1. Schematic representation of the steps involved in tumor cell invasion
Upon dissociating from adjacent cells and detaching from the basement membrane, malignant cells extend filopodia and lamellipodia, plasma membrane-covered protrusions of actin-rich cytoplasm, into regions of degraded connective tissue matrix. These protrusions adhere to the surrounding matrix components to initiate tumor cell motility. Migration through the connective tissues occurs through a repeating cycle of tumor cell extension at the front of the cell, adhesion to matrix, contraction of actin-myosin filaments, and release of cell attachments at the rear.
In addition to invading connective tissue stroma, malignant tumor cells can invade the perineurium. Particular types of malignant cells are more prone to do this than others. Invasion of the perineurium allows unimpeded tumor extension along the nerves. Invasion of lymphatic vessels and blood vessels results in lymphatic and hematogenous dissemination, respectively, with the production of distant metastases.
Detachment of malignant cells from each other and from the underlying basement membrane, the first step in tumor cell invasion, is a consequence of altered cell-cell and cell-matrix adhesion. E-cadherin, a principal component of adherens junctions in epithelial cells, forms complexes with various members of the catenin family to promote cell-cell adhesion in normal cells. The catenins link E-cadherin to the actin filament network. Downregulation of cell-cell junctions occurs either through decreased E-cadherin expression or increased Wnt signaling, which depletes beta-catenin from junctional complexes.
Integrins within hemidesmosomes promote anchorage-dependent growth and survival of normal cells by signaling cooperatively with growth factor receptors to activate cell proliferation and survival pathways. Tumor cell detachment from the basement membrane results from downregulation of cell-surface integrins or dissociation of adhesion complexes.
To disrupt the underlying basement membrane and degrade surrounding matrix, tumor cells upregulate expression of a number of proteases, including serine-, cysteine-, aspartyl- and matrix metalloproteinases (MMPs). Plasminogen activators (plasminogen-activating system) are among the group of serine proteases. Both MMPs and plasminogen activators have specific inhibitors involved in their regulation. Both are known to bind tumor cell surface receptors, thereby localizing matrix degradation to the invading front of the tumor, and proteasemediated cleavage of some cell surface receptors also contributes to tumor cell invasion. In addition to protease secretion by the tumor cells themselves, tumor-stromal interactions induce production of MMPs by surrounding fibroblasts and macrophages.
The migration of tumor cells is stimulated by secreted cytokines and growth factors. The cleavage products of some matrix components are also likely to promote tumor cell migration, as some are known to have chemotactic activity. In addition, alterations in Wnt and integrin signaling associated with cell-cell and cell-matrix detachment, respectively, also promote tumor cell migration. Growth factors can induce not only dissociation of adhesion complexes but also a relocalization of specific integrins to the leading edge of tumor cells. Integrins at the leading edge signal through RAS motility pathways to promote tumor cell migration. Wnt signaling not only leads to cell-cell detachment but also promotes tumor cell migration by inducing nuclear localization of beta-catenin with subsequent activation of genes involved in cell motility.
Fig. 2. Photomicrograph of an invasive ductal carcinoma of breast, the most common form of invasive breast cancer. The portion of the tumor undergoing invasion of the connective tissue stroma (closed arrow) is shown adjacent to a residual component of noninvasive ductal carcinoma in situ (open arrow)
The size of the invasive tumor is used in tumor staging to predict the likelihood of tumor recurrence after treatment. The size of the invasive tumor is essentially a quantitative measure of invasion, and tumor size is one of the main determinants of the type and extent of therapy. Microinvasion (less than 1 mm of invasion) has minimal risk of tumor progression after treatment. Greater amounts of invasion increase the likelihood of both local and systemic recurrences (Fig. 2). Tumor invasion can extend beyond the area of involvement identified clinically, resulting in local recurrence following surgical excision. Invasion of lymphatic and blood vascular channels can lead to distant metastasis with widespread dissemination of tumor cells. Although distant metastasis is the cause of death for most cancer patients, extensive local invasion of a malignant neoplasm can compress adjacent vital structures and cause death in the absence of distant metastasis.
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