Abstract
Tumorigenesis can be considered as pathologically misappropriated tissue regeneration. In this review we will address some unresolved issues that support this concept. First, we will address the issue of the identity of cancer-initiating cells and the presence of cancer stem cells in growing tumors. We will also ask are there rare and distinct populations of cancer stem cells in established tumor cell lines, or are all of the cells cancer stem cells? Second, the most important clinical problem with cancer is its metastasis, and here a challenging question arises: by employing radio-chemotherapy for tumor treatment, do we unintentionally create a prometastatic microenvironment in collateral organs? Specifically, many factors upregulated in response to radio-chemotherapy-induced injury may attract highly migratory cancer cells that survived initial treatment. Third, what is the contribution of normal circulating stem cells to the growing malignancy? Do circulating normal stem cells recognize a tumor as a hypoxia-damaged tissue that needs vascular and stromal support and thereby contribute to tumor expansion? Fourth, is it reasonable to inhibit only one prometastatic ligand–receptor axis when cancer stem cells express several receptors for several chemotactic factors that may compensate for inhibition of the targeted receptor? Fifth, since most aggressive cancer cells mimic early-development stem cells, which properties of embryonic stem cells are retained in cancer cells? Would it be reasonable to inhibit cancer cell signaling pathways involved in the migration and proliferation of embryonic stem cells? We will also briefly address some new players in cancerogenesis, including extracellular microvesicles, bioactive phospholipids, and extracellular nucleotides.
Highlights
Cancer is a serious clinical challenge, and, despite significant efforts to solve this problem, we are far from developing cures for the most aggressive solid malignancies and refractory leukemia
We found that sorted cells enriched for stem cell markers possessed higher migratory and adhesive properties than cells negative for these markers [24, 25]. This result supported the functional properties thought to be characteristic of metastatic cancer stem cells [26]. When we sorted these cells as single cells according to their respective phenotypes including cells that did not expressed putative cancer stem cell markers and expanded them ex vivo under limiting dilution conditions, we found that all gave rise to clones that were comparable to the parental cell lines in terms of surface antigen expression, and, importantly, all four phenotypes were again reestablished in the expanded clones [24, 25]
In our studies performed with the human ovarian cancer cell line A2780, we found that total body irradiation or administration of cisplatin increases the metastatic spread of human ovarian cancer cells transplanted into immunodeficient mice compared with control animals unexposed to irradiation or cisplatin [29, 30]
Summary
Cancer is a serious clinical challenge, and, despite significant efforts to solve this problem, we are far from developing cures for the most aggressive solid malignancies and refractory leukemia. The most urgent questions concern (i) the cells of origin for developing malignancies, (ii) cancer resistance to therapy and metastasis, (iii) the supportive role of normal stem cells in developing tumors, (iv) the fact that most primitive cancers mimic many features of embryonic cells, and (v) the emerging involvement of new players in cancerogenesis, including extracellular microvesicles (ExMVs), complement cascade cleavage fragments, bioactive phospholipids, and extracellular nucleotides [14,15,16,17,18]. We demonstrated that a similar effect occurs in vivo after radio-chemotherapy in an experimental model of lung cancer [31] Based on this finding, we propose that a radiochemotherapy-induced prometastatic microenvironment plays an important role in the metastasis of cancer cells that are resistant to treatment and have characteristics of highly migratory cancer stem cells. This novel observation may explain the preferential metastasis of cancer cells to lymph or body cavities where the concentration of fibrinogen is relatively low, and vitronectin is not bound to fibrinogen and as free protein can chemoattract cancer cells [49]
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