Targeting To Cancer Cells

In a very simplified sense, cancers occur through dysregulation of normal cell function. The body is designed to correct tissue defects following damage, to expand selected immune cells in response to a pathogen, and to compensate for perceived deficiencies in one cell type by altering the phenotype of another such as in stem cell recruitment. Each of these processes is mediated by (normally) regulated events that allow cells to lose their differentiated phenotype with restrained growth characteristics and acquire a replication-driven phenotype. A lack of re-differentiation into a growth-restrained, differentiated phenotype is the paradigm of cancer. Repair of an epithelial wound is a good example of this phenomenon (Figure 3.3). It is the lack of re-differentiation and continued responsiveness of these cells to growth factors and growth activators that supports and maintains the cancer phenotype. Extensive genomic differences between differentiated and non-differentiated forms of the same cell account for the differences observed between these two cell phenotypes.67

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FIGURE 3.3 Loss and recovery of barrier function associated with normal epithelia. (a) Epithelia express tight junctions (□) and associate at their base with a complex of proteins known as the basement membrane ( ). (b) Damage to epithelia increases responses to growth factors and results in differentiated epithelial cells that can freely divide. (c) Cell division continues until damaged area is covered. (d) Cell-cell contacts such as adherens junctions, tight junctions, and gap junctions have been shown to suppress growth and stimulate re-differentiation.

Many of the differences between replicating and non-replicating cells are associated with surface and metabolic properties that can be used to discriminate between differentiated (normal) and de-differentiated (cancer) cells. One of the biggest concerns using this information to target cancer cells is that non-cancerous cells undergoing normal and necessary repair processes may transiently express these same targets. For example, herceptin is an antibody that binds to her2/neu receptors that are over expressed on the surfaces of cancer cells. Unfortunately, this antibody can also target normal cardiac cells undergoing repair induced by the actions of a common anti-cancer agent, doxorubicin; patients on doxorubicin treatment are placed on an extended washout period prior to exposure to herceptin. Therefore, nanoparticles having a cytotoxic capacity and targeted using the herceptin antibody could result in cardiomyopathy. Fortunately, the high, transient, systemic levels of doxorubicin associated with direct administration can be muted by administration in nanomaterials such as liposomes, reducing the risk of cardiomyopathy.68 That many surface and metabolic properties are the same for both cancer cells of a particular cell type and the undifferentiated form of that cell type during normal cell function must be appreciated as one examines potential cancer cell-targeting strategies for nanoparticles.

The general issues raised above concerning safety aspects of targeting cancer cells highlight concerns of selecting a strategy that properly accounts for unique cell surface properties and metabolic activities of cancer cells relative to normal cells. All too frequently, normal cells can undergo processes (e.g., wound repair) that will transiently transform them into a cell with surface properties or metabolic characteristics indistinguishable from a cancer cell. In some aspects, these altered surface properties and metabolic activities are intertwined. Alterations in metabolic properties can induce increased expression of nutrient uptake pathways and catabolic proteins that assist in nutrient absorption to sustain the accelerated growth rate of cancer cells. Because some of these components are present at the cell surface, a cancer cell's composition and profile are modified by their presence. From an opposing perspective, increased surface expression of components such as growth factor receptors will shift the metabolic activity of a cancer cell following activation of that receptor (either constitutive activation or ligand-induced activation).

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