Understanding the processes involved in the development, progression, and spread of cancer is essential in developing effective therapeutic interventions. This paper attempts to elucidate the processes involved in tumor progression and metastasis. This objective will be accomplished by examining the basic biology of cancerous cells and briefly delineating the processes involved in the metastatic cascade.
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Basic Biology of Cancerous Cells
The presence of signaling pathways that control cell hemostasis subjects normal cells to the regulation of proliferation, differentiation, and apoptosis. Tumors develop when a normal cell undergoes an oncogenic transformation, which gives it autonomy from extracellular control resulting in unbridled growth and proliferation (Hejmadi, 2010). Cellular metabolism is an essential driver of carcinoma proliferation. Cancerous cells typically produce large volumes of Adenosine Triphosphate (ATP) and biosynthetic precursors to facilitate this rapid growth. Rapid proliferation typically generates high levels of oxidative stress that would kill normal cells (Cairns, 2011). Thus, cancerous cells must adapt themselves from the effects of this toxic environment to continue their rapid growth through metabolic transformation (Kivet et al., 2014). Cells that manage to survive the toxic environment form the basis of a second mutation, which leads up to a mildly aberrant stage in tumor progression. Subsequent rounds of mutation and expansion lead to the formation of a tumor mass at the primary site. The resultant cells must break through the basement membrane to promote metastasis at a distant location.
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Invasion and metastasis
Carcinogenic cells in the tumor mass break through the basement membrane to invade the surrounding stroma via several mechanisms. One such mechanism is through Epithelial-Mesenchymal Transition (EMT) (Valastyan & Weinberg, 2011). The presence of E-cadherin mediated intercellular junctions in the basement membrane prevents dissociation of epithelial cells from each other. Through EMT transcription factors, tumor cells can dissolve tight junctions, which leads to loss of cell polarity, individual cell separation, and increased permeability.
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Tumor cells traveling in lymphatic and vascular circulation may get physically tapped in the microvasculature of distant organs or follow a predetermined inclination to lodge at specific sites (Auguste et al, 2007). Remaining carcinoma cells may undergo extravasation at remote sites, where they cross from the vessel lumen into the parenchyma through the action of specific factors that induce vascular hyper-permeability (Valastyan & Weinberg, 2011). Clinical trials investigating metastasis indicate that tumor cells may suffer attrition over time, undergo prolonged dormancy, or proliferate rapidly to form large colonies depending on the suitability of the microenvironment at the distant site. For instance, melanoma cells form substantial macroscopic colonies in subcutaneous grafts of lung tissue but fail to do so in identical subcutaneous renal tissue (Valastyan & Weinberg, 2011). Thus, the ability of the cells to survive unfamiliar sites is critical to the success or failure of metastatic processes.
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Therapeutic targeting of invasion and metastasis
Most therapeutic agents targeting the hallmark of invasion and metastasis attempt to block intravasation from the primary tumor. However, studies have demonstrated that these agents typically fail to respond to already disseminated tumors (Holland et al., 2010). Furthermore, it has been demonstrated the most cancer patients typically have significant, undetectable numbers of already disseminated tumor cells in circulation and distant organs (Valastyan & Weinberg, 2011). Given the evident vulnerability of tumor cells at metastatic sites. Thus, an effective therapeutic agent should attempt to prevent the survival of disseminated cells at the distant site.
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Oncogenic transformation of normal cells initiates unbridled proliferation and growth. Cells that can survive the toxic microenvironment created by robust metabolic processes form precursors for mutations, selective expansion processes, which leads to the generation of a tumor mass. Cells from the mass break through the basement membrane utilizing EMT transcription factors, travel in circulation and spread to distant sites. At distant organs, tumor cells encounter an unfamiliar environment that renders them vulnerable to attrition and dormancy. This phenomenon obviates the use of therapeutic interventions that aim to preclude the survival of these cells at these sites.
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