Cancer Stem Cells, Endothelial Progenitors, and Mesenchymal Stem Cells: “Seed and Soil” Theory Revisited

摘要

Isolation of putative cancer stem cells (CSCs) in various tumors has generated much excitement among researchers who consider these cells the potential “culprits” behind resistance to conventional therapy. Both cancer and cardiovascular disease are believed to be stem cell disorders involving circulating endothelial progenitors (CEPs) and mesenchymal stem cells (MSCs). CD133 and CD44, markers of CSCs in many tumors, also enrich CEPs and MSCs, respectively. We propose an integrated tumorigenesis model that involves all three interdependent stem cell (CSC, CEP, MSC) compartments by revisiting the “seed and soil” model. Developing therapeutics that can effectively target CSCs and spare normal cardiovascular tissue will remain a challenge. Preliminary laboratory and clinical data on monitoring and targeting colon CSCs, using such a modeling system, are discussed. More than a century ago, Virchow and Paget indirectly implied the existence of cancer stem cells (CSCs) 1 and a CSC niche, 2 respectively. The term “cancer stem cells” was coined in the early 1980s, 3 but research in the field was hampered by the lack of specific markers, cell-sorting technology, and the extremely low frequency of CSCs. The first isolation of putative CSCs in acute myelogenous leukemia (AML) by Dick and colleagues in 1994 4 spurred a wave of discoveries of CSCs in acute lymphocytic leukemia (ALL), 5 , 6 chronic myelogenous leukemia (CML), 7 , 8 multiple myeloma, 9 and in cancers of the colon, 10 – 12 breast, 13 prostate, 14 – 16 brain, 17 , 18 head and neck, 19 retina, 20 lung, 21 , 22 pancreas, 23 melanoma, 24 , 25 kidney, 26 and liver. 27 , 28 Researchers postulated that CSCs might be the “culprits” capable of evading conventional therapy; thus, eradication of CSCs could lead to complete cure. 29 , 30 However, CSCs are quiescent or slow cycling, 31 , 32 they overexpress antiapoptotic proteins, 24 , 25 , 33 possess multidrug resistance proteins, 24 , 25 , 34 , 35 and are characteristically similar to normal stem cells, except that their ability to differentiate is impaired. 4 – 29 In 1997, Asahara et al first identified bone-marrow derived circulating endothelial progenitors (CEPs) vital in postnatal physiologic and pathologic angiogenesis. 36 In the same year, Yin et al discovered CD133, a member of the prominin family that identifies and enriches CEPs. 37 Two large prospective studies showed that decreased CEP levels independently predict increased cardiovascular death and correlate with all known cardiovascular risk factors. 38 , 39 Conversely, elevated CEP levels were found in patients with leukemia, 40 myeloma, 41 , 42 myelodysplastic syndrome, 43 cancers of the lung, 44 breast, 45 , 46 liver, 47 colon and rectum, 48 – 50 prostate, 49 kidney, 26 and in infantile hemangioma. 51 Furthermore, the presence of elevated levels of CEPs or CD133 mRNA is predictive of poor outcomes and death in certain tumors. 44 , 47 – 49 , 52 Circulating endothelial progenitors are known to form the premetastatic niche essential in the earliest step to tumor angiogenesis, 53 and it has been shown that targeting CEPs inhibits the development of macrometastases from micrometastases in mouse lung metastasis models. 54 Moreover, it has been demonstrated that bone marrow-derived stem cells can transdifferentiate into endothelial precursor cells with the potential to acquire mutations and contribute “cancerous” microvascular endothelial cells to tumor vessels. 55 In 1997, Zohar and others identified mesenchymal stem cells (MSCs) using CD44, a glycoprotein ligand that binds with hyaluronate and E-selectin. 56 , 57 Variant forms of CD44 are expressed in many human cancers and correlate with cancer outcomes in certain tumors. 58 – 67 Interestingly, CD133 and CD44 have both been used to isolate CSCs in many tumors. 4 – 25 The purpose of this review is t