Cancer Stem Cells in Hematological Disorders: Current and Possible New Therapeutic Approaches

Abstract

An increasing body of evidence has shown that hematologic malignancies, alike normal hematopoiesis, has a hierarchical structure including a stem cell compartment with self renewal capability, endowed in a neoplastic niche bearing resemblance to its normal hematopoietic counterpart. According to experimental data on NOD-SCID mice, leukemic stem cells are characterized by a CD34+/CD38- surface profile and account for 1 in 10(3) to 1 in 10(6) of the total amount of leukemic cells. The available knowledge about leukemic stem cells (LSC) has arisen the question as to whether some targeting of LSC is achieved by current treatments; the answer is dubitative at best, with the possible exception of arsenic trioxide in promyelocytic leukemia. On the other side, the unsatisfactory results in the treatment of many hematological neoplasms has prompted many research groups to find out whether direct targeting of LSC, possibly in its niche, would result in an improvement in cure rates. This approach implies the identification of LSC specific markers, clearly distinct from their normal counterpart in order to spare normal hematopoietic stem cells. Adhesion/surface antigens, metabolic pathways involved in LSC survival and renewal, telomerase, commonly mutated genes and epigenetic phenomena have been investigated as candidate targets for newer therapeutic strategies. So far, most of the possibly effective agents have been studied in experimental models only. FLT-3 inhibitors account for a notable exception since they have resulted effective in vivo in AML with mutated, but not over expressed, FLT-3. A main task for the future is to find out whether some common LSC specific markers would be identifiable in a substantial proportion of AML cases, or whether each AML case shows a unique fingerprint of markers. In the latter event, targeting of LSC could result in an arduous task.

What makes cancer stem cell markers different?

“…It is not intended as a full review.Abbreviations: AdSC adult stem cell, CSC cancer stem cell, EnProgC endothelial progenitor cell, ESC embryonic stem cell, HProgC hematopoietic progenitor cell, HSC hematopoietic stem cell, ProgC progenitor cell, PSC pluripotent stem cell, iPSC induced pluripotent stem cell.,Ginestier et al 2007; 2, Sangiorgi and Capecchi Sangiorgi and Capecchi 2008; 3, Lukacs et al Lukacs et al 2010; 4, Pontier and Muller Pontier and Muller 2009; 5, Taddei et al Taddei et al 2008; 6, Krause et al Krause et al 1996; 7, Furness et al Furness et al 2006; 8, Tardio Tardio 2009; 9, Annaloro et al Annaloro et al 2011; 10, Srour et al Srour et al 1991; 11, Basso and Timeus Basso and Timeus 1998; Günthert et al 12, Günthert et al Günthert et al 1991; Zöller 13, Zöller Zöller 2011; 14, Singh et al Singh et al 2001; 15, Takaishi et al Takaishi et al 2009; 16, Zhang et al Zhang et al 2008; 17, Augello et al Augello et al 2010; 18, Salcido et al Salcido et al 2010; 19, Ponnusamy and Batra Ponnusamy and Batra 2008; 20, Liu et al Liu et al 2006; 21, Mizrak et al Mizrak et al 2008; 22, Ricci-Vitani et al Ricci-Vitani et al 2007; 23, Kemper et al Kemper et al 2010; O’Brien et al 24, O’Brien et al O’Brien et al 2007; 25, Bunting Bunting 2002; 26, Monzani et al Monzani et al 2007; 27, Krupkova et al Krupkova et al 2010; Dell’Albani 28, Dell’Albani Dell’Albani 2008; 29, Monk and Holding Monk and Holding 2001; 30, Carpenter et al Carpenter et al 2003.…”

Intrinsic targeting strategies against acute myeloid leukemic stem cells

“…Prevention of degradation of inhibitor of κB (IκB) by the proteasome inhibitor bortezomib enhances the anti-NF-κB effect [25]. Also, NF-κB could be inhibited in LSCs by parthenolide (PTL), leading to decreased engraftment of leukemic cells into NOD/SCID mice, but the poor water solubility of PTL remains a problem.…”

“…The effect of SALL4 is mediated mainly through the Bmi-1 gene. Several observations illustrate the role of SALL4 in leukemia including the reduced ability of leukemic cell lines with a defect in SALL4 to initiate leukemia in NOD/SCID mice [25]. Using SALL4 as a target to initiate apoptosis of LSCs is attractive, but the high risk of multi-organ involvement raises doubts about this strategy.…”

Cancer Stem Cells

“…Currently available therapies targeting molecular markers of diseases such as bcr-abl inhibitors (for CML) or Jak-2 inhibitors (for other myeloproliferative disorders) appear to have minimal effects on CSCs. 59,60 If only a defined subpopulation of cells within the tumor can initiate and maintain malignant growth, they are the cells that must be effectively targeted to achieve a definitive, long-term "cure". Thus novel therapeutic approaches will be needed to eradicate these CSCs.…”