Axel Schulenburg

Neoplastic stem cells: a novel therapeutic target in clinical oncology.

Cancer is among the leading causes of morbidity and mortality in the Western world. Despite recent advances, most therapeutic approaches fail to eradicate the entire neoplastic clone. The remaining cells often develop metastasis and/or recurrences and therefore may represent attractive targets of therapy. A new exciting concept in this regard suggests that each neoplasm represents a heterogeneous population of cells that pertain to long‐term tumor growth both in vivo in the natural host and in experimental animals. This concept postulates the existence of small fractions of ‘tumor stem cells’ that exhibit a capacity for self‐renewal and unlimited growth and therefore are distinct from their progeny. Based on these hypotheses, the targeting of neoplastic stem cells is considered indispensable for eradication of the entire clone and for the development of curative treatment approaches. However, tumor stem cells often may be quiescent cells and may express a different profile of targets compared with ‘more mature’ tumor cells. Therefore, current efforts have attempted to characterize target expression profiles in cancer stem cells in various malignancies. In the this review, the authors have provided a brief summary of the current knowledge of neoplastic stem cells and the application of respective concepts in translational oncology with the ultimate objective of improving anticancer therapy. Cancer 2006.

ABO mismatch increases transplant-related morbidity and mortality in patients given nonmyeloablative allogeneic HPC transplantation

BACKGROUND: ABO mismatch has not been thought to affect the outcome of patients undergoing myeloablative conditioning and allogeneic HPC transplantation. Data on transplant‐related complications after ABO‐mismatched transplantation after nonmyeloablative conditioning are limited.

CD44‐positive colorectal adenoma cells express the potential stem cell markers musashi antigen (msi1) and ephrin B2 receptor (EphB2)

The majority of colorectal adenomas contain a mutation in the APC gene activating the wnt pathway. As wnt signalling preserves stem cell functions, it would be expected that stem cells would be enriched in adenomas. We have shown expression of the wnt target gene CD44, which may characterize the expanded stem cell compartment, in colorectal tumours. To investigate this possibility, we performed an immunohistological survey of CD44 expression in relation to the proliferation marker Ki67 and apoptosis in colorectal tumour tissue, and have isolated a CD44‐positive subpopulation of the human colorectal adenoma cell line LT97 for cell biological analysis. In tissues, CD44 expression was not related to Ki67, but was associated with lower apoptosis in the CD44‐positive areas. CD44‐positive and ‐negative populations isolated from LT97 cultures were identical in their Ki‐ras and p53 status but differed in their growth and survival characteristics. While CD44‐positive cells attached and grew to reconstitute the original culture, the CD44‐negative cells rapidly underwent apoptosis and were unable to resume growth. In comparison to unsorted growing LT97 cells, the CD44‐positive cells had shifted ß‐catenin into the nucleus and expressed ß‐catenin target genes, such as ephrin B receptor (ephB2) and musashi antigen (msi1). By contrast, CD44‐negative cultures contained no cells with nuclear β‐catenin. In summary, the CD44‐positive cells accumulating in colorectal tumours have increased survival capacity both in vivo and in vitro. They also express markers typical of colorectal progenitor cells, msi1 and ephB2, in the premalignant progenitor population. Copyright

Cancer stem cells in basic science and in translational oncology: can we translate into clinical application?

Since their description and identification in leukemias and solid tumors, cancer stem cells (CSC) have been the subject of intensive research in translational oncology. Indeed, recent advances have led to the identification of CSC markers, CSC targets, and the preclinical and clinical evaluation of the CSC-eradicating (curative) potential of various drugs. However, although diverse CSC markers and targets have been identified, several questions remain, such as the origin and evolution of CSC, mechanisms underlying resistance of CSC against various targeted drugs, and the biochemical basis and function of stroma cell-CSC interactions in the so-called ‘stem cell niche.’ Additional aspects that have to be taken into account when considering CSC elimination as primary treatment-goal are the genomic plasticity and extensive subclone formation of CSC. Notably, various cell fractions with different combinations of molecular aberrations and varying proliferative potential may display CSC function in a given neoplasm, and the related molecular complexity of the genome in CSC subsets is considered to contribute essentially to disease evolution and acquired drug resistance. In the current article, we discuss new developments in the field of CSC research and whether these new concepts can be exploited in clinical practice in the future.

Neoplastic stem cells: Current concepts and clinical perspectives

Neoplastic stem cells have initially been characterized in myeloid leukemias where NOD/SCID mouse-repopulating progenitors supposedly reside within a CD34+/Lin- subset of the malignant clone. These progenitors are considered to be self-renewing cells responsible for the in vivo long-term growth of neoplastic cells in leukemic patients. Therefore, these cells represent an attractive target of therapy. In some lymphoid leukemias, NOD/SCID mouse-repopulating cells were also reported to reside within the CD34+/Lin- subfraction of the clone. More recently, several attempts have been made to transfer the cancer stem cell concept to solid tumors and other non-hematopoietic neoplasms. In several of these tumors, the cell surface antigens AC133 (CD133) and CD44 are considered to indicate the potential of a cell to initiate permanent tumor formation in vivo. However, several questions concerning the phenotype, self-renewal capacity, stroma-dependence, and other properties of cancer- or leukemia-initiating cells remain to be solved. The current article provides a summary of our current knowledge on neoplastic (cancer) stem cells, with special emphasis on clinical implications and therapeutic options as well as a discussion about conceptual and technical limitations.

Lung Transplantation for Bronchiolitis Obliterans After Allogeneic Hematopoietic Stem Cell Transplantation: A Single-center Experience

Background Bronchiolitis obliterans (BO) is a detrimental late pulmonary complication after allogeneic hematopoietic stem cell transplantation (HCT) associated with chronic graft-versus-host disease (cGvHD). When systemic immunosuppressive treatment fails to improve, severe BO patients should be considered for lung transplantation (LuTX). We present seven patients undergoing LuTX for severe refractory BO after HCT. Methods Seven patients with hematologic malignancies developed severe cGvHD with lung involvement presenting as BO after allogeneic HCT. Evaluation for LuTX was initiated after failure of a median of 4 immunosuppressive regimens. Results Between 1996 and 2012, seven patients with severe refractory BO were evaluated for LuTX. The median time from HCT to diagnosis of chronic lung GvHD was 8.2 months (range, 3.7–16.6). At a median time of 18.1 months (range, 6–120) after diagnosis of BO, six patients received a bilateral sequential LuTX, and one patient received a single LuTX. Six postoperative courses were uneventful; the patient with single LuTX died from septic multiorgan failure. Three LuTX recipients had a mild acute rejection after one to three months after LuTX, and one patient experienced fatal chronic rejection and hemolytic uremic syndrome. At present, three (43%) LuTX recipients remain alive at a median observation time of 26 months (range, 1 month–16 years) after LuTX. The median overall survival from LuTX was 24 months (95% CI, 0.5–78); the median overall survival time after allogeneic HCT is 98 months (95% CI, 46–198). Conclusion This case series illustrates that LuTX is a possible therapeutic option for selected patients with severe treatment-refractory BO.

Brief Report: Practicability and safety of amphotericin B deoxycholate as continuous infusion in neutropenic patients with hematological malignancies

Fungal infections are a major cause of morbidity and mortality in patients with hematological malignancies. Candida and Aspergillus species are the most important opportunistic fungal pathogens in this patient population. Amphotericin B is the treatment of choice, but its administration is often hampered by severe side-effects, which may be reduced by continuous infusion of this drug. We describe 17 consecutive patients with hematological malignancies, suffering from fever of unknown origin with possible fungal infections, treated with amphotericin B as continuous infusion compared with a control group of 10 patients treated with conventional rapid infusion of amphotericin B over 2 - 6 h. No acute side-effects or severe nephrotoxicity were observed during continuous infusion of amphotericin B. Target doses were reached faster in patients with continuous infusion of amphotericin B than in patients with rapid infusion. We conclude that continuous infusion of amphotericin B is safe in neutropenic patients with hematological malignancies.

Autocrine fibroblast growth factor 18 signaling mediates Wnt‐dependent stimulation of CD44‐positive human colorectal adenoma cells

Expansion of a stem‐like subpopulation with increased growth and survival potential is thought to drive colorectal tumor growth and progression. We investigated a CD44‐positive (CD44(+)) subpopulation with extended growth and survival capacity in the human colon adenoma cell line LT97. This subpopulation expressed elevated levels of fibroblast growth factor 18 (FGF18) and fibroblast growth factor receptor FGFR3‐IIIc. Expression levels of the FGFR3‐IIIb, which does not bind FGF18, were similar in CD44(+) and CD44(−). Addition of FGF18 to the medium or its overexpression from an adenoviral vector increased the colony formation capacity of CD44(+) threefold, and stimulated phosphorylation of ERK and GSK3β in both total LT97 populations and CD44(+) cells. FGFR3 signaling blockade by expression of a dominant‐negative FGFR3‐IIIc mutant led to inhibition of both colony formation and down‐stream signaling in the CD44(+) cells. CD44(−) cells did not respond. Blockade of the wnt‐pathway by a dominant‐negative Tcf4‐mutant inhibited FGFR3 activation in LT97 cells as well as in HT29 colorectal cancer cells. The chemical wnt‐inhibitor sulindac sulfide amide inhibited expression of FGF18 and FGFR3‐IIIc and led to inhibition of receptor activation to less than 30% of control treated cells, both in LT97 and HT29 cultures. Our results demonstrate that an FGF18/FGFR3‐IIIc autocrine growth and survival loop is up‐regulated in a wnt‐dependent manner and drives tumor cell growth in a subpopulation of colon adenoma cells. This subpopulation can be regarded as a precursor of colon cancer development and can be targeted for CRC‐prevention by blocking either wnt‐ or FGFR3‐signaling.

Fatal skin and pulmonary infection caused by Hormographiella aspergillata in a leukaemic patient: case report and literature overview

Invasive systemic fungal infections are a major cause of morbidity and mortality in patients after hematopoietic stem cell transplantation. We report the case of a fatal infection with Hormographiella aspergillata in a patient undergoing allogenic peripheral blood stem cell transplantation for acute myeloid leukaemia.

Tumor-Stammzellforschung – Basis und Herausforderung für Diagnostik und Therapie

Biological features of tumor cells relevant to progression, metastasis, and prognosis in cancer patients have been investigated for many years. During the past few years, the concept of tumor stem cells has gained widespread acceptance. The cancer stem cell (CSC) model is based on the observation that continuous growth of tumors depends on a small population of immature neoplastic cells with unlimited proliferative potential. In contrast to these CSC, more mature clonal cells in the same neoplasm undergo apoptosis and die after a variable number of cell divisions. The self-renewal capacity of CSC plays a central role in this scenario and enables permanent tumor cell repopulation in vivo in patients as well as in experimental animals, e.g., immunodeficient mice. Based on the stem cell concept, it is clear that the success of an anti-neoplastic approach depends on efficient targeting and elimination of CSC. An important aspect of CSC is their intrinsic resistance against conventional drugs. Therefore, a major focus in current research is molecular targets and their expression in CSC, with the goal to use targeted drugs for CSC elimination. It is the hope for the future that therapeutic approaches involving CSC-targeting concepts will lead to sustained remission and thus improvement of prognosis in leukemia and cancer patients.SummaryBiological features of tumor cells relevant to progression, metastasis, and prognosis in cancer patients have been investigated for many years. During the past few years, the concept of tumor stem cells has gained widespread acceptance. The cancer stem cell (CSC) model is based on the observation that continuous growth of tumors depends on a small population of immature neoplastic cells with unlimited proliferative potential. In contrast to these CSC, more mature clonal cells in the same neoplasm undergo apoptosis and die after a variable number of cell divisions. The self-renewal capacity of CSC plays a central role in this scenario and enables permanent tumor cell repopulation in vivo in patients as well as in experimental animals, e.g., immunodeficient mice. Based on the stem cell concept, it is clear that the success of an anti-neoplastic approach depends on efficient targeting and elimination of CSC. An important aspect of CSC is their intrinsic resistance against conventional drugs. Therefore, a major focus in current research is molecular targets and their expression in CSC, with the goal to use targeted drugs for CSC elimination. It is the hope for the future that therapeutic approaches involving CSC-targeting concepts will lead to sustained remission and thus improvement of prognosis in leukemia and cancer patients.ZusammenfassungSeit vielen Jahren wird die Biologie der Tumorzellen und ihre Bedeutung für Tumorprogression, Metastasierung und Prognose der Tumorpatienten erforscht. In den letzten Jahren gewinnt dabei das Konzept der sogenannten Tumor-Stammzellen immer mehr an Bedeutung. Dieses Modell basiert auf der Beobachtung, dass das kontinuierliche Wachstum von Tumoren und Leukämien von einer kleinen Population sehr unreifer neoplastischer Zellen, den Tumorstammzellen abhängt, während die reiferen Zellen der Neoplasie nach einer variablen Anzahl von Zellteilungen über Apoptose absterben. Die Selbsterneuerungsfähigkeit der Tumorstammzellen spielt dabei eine zentrale Rolle und ermöglicht eine dauerhafte Repopulation in vivo im Patienten und in experimentellen Modellen wie z.B. in immunsupprimierten Mäusen. Somit ist auch klar, dass antineoplastische Therapien nur dann ein kuratives Potential haben, wenn die Tumorstammzellen getroffen werden. Ein wichtiger Aspekt ist deren intrinsische Resistenz gegenüber konventionellen Medikamenten. Daher versucht man, molekulare Targets und Target-Expressionsprofile in neoplastischen Stammzellen zu erkennen und in therapeutischen Ansätzen zu nutzen. Es ist zu erhoffen, dass die Anwendung der Tumorstammzell-Konzepte zu einer nachhaltigen Verbesserung der Therapie von Leukämien und Tumorerkrankungen führen wird.