CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance

ABSTRACTMetastasis is the primary cause of cancer patient morbidity and mortality but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patients' tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven by a cancer stem-like cell or tumor progenitor cell, while recurrence at a secondary site is driven by metastatic cancer stem cells or metastasis-initiating cells. Ongoing efforts are aimed at identifying and characterizing these stem-like cells driving recurrence and metastasis. One potential marker for the cancer stem-like cell subpopulation is CD117/c-kit, a tyrosine kinase receptor associated with cancer progression and normal stem cell maintenance. In our analyses, CD117 was expressed in several tissues and was highly expressed in bone marrow progenitor cells. Also, we uncovered that CD117 gene amplifications and mutations occurred in multiple cancers. Further, activation of CD117 by its ligand stem cell factor (SCF; kit ligand) in the progenitor cell niche stimulates several signaling pathways driving proliferation, survival, and migration. These signaling pathways were commonly altered in patients with CD117 amplifications and mutations. Here, we examine evidence that the SCF/CD117 signaling axis controls cancer progression through the regulation of stemness and resistance to tyrosine kinase inhibitors.AbbreviationsAMLacute myeloid leukemiaCMLchronic myeloid leukemiaCTCcirculating tumor cellCSCcancer stem cellDTCdisseminated tumor cellGISTgastrointestinal stromal tumorHSChematopoietic stem cellSCFstem cell factorTKItyrosine kinase inhibitor

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The Cancer Stem Cell Marker Aldehyde Dehydrogenase Is Required to Maintain a Drug-Tolerant Tumor Cell Subpopulation

Cancer Research ◽

10.1158/0008-5472.can-13-3456 ◽

2014 ◽

Vol 74 (13) ◽

pp. 3579-3590 ◽

Cited By ~ 129

Author(s):

Debasish Raha ◽

Timothy R. Wilson ◽

Jing Peng ◽

David Peterson ◽

Peng Yue ◽

...

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Tumor Cell ◽

Aldehyde Dehydrogenase ◽

Stem Cell Marker ◽

Cell Subpopulation ◽

Cancer Stem Cell Marker ◽

Cell Marker

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The Met tyrosine kinase receptor as a therapeutic target and a potential cancer stem cell factor responsible for therapy resistance

Oncology Reports ◽

10.3892/or.2016.5297 ◽

2016 ◽

Vol 37 (2) ◽

pp. 647-656 ◽

Cited By ~ 11

Author(s):

Katarzyna Miekus

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Tyrosine Kinase ◽

Therapeutic Target ◽

Stem Cell Factor ◽

Therapy Resistance ◽

Tyrosine Kinase Receptor ◽

Potential Cancer

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Signaling Through the Interaction of Membrane-Restricted Stem Cell Factor and c-kit Receptor Tyrosine Kinase: Genetic Evidence for a Differential Role in Erythropoiesis

Blood ◽

10.1182/blood.v91.3.879 ◽

1998 ◽

Vol 91 (3) ◽

pp. 879-889 ◽

Cited By ~ 62

Author(s):

Reuben Kapur ◽

Manus Majumdar ◽

Xiangli Xiao ◽

Monica McAndrews-Hill ◽

Karen Schindler ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Stromal Cells ◽

Stem Cell Factor ◽

Progenitor Cell ◽

Erythropoietin Receptor ◽

Soluble Form

Abstract Mutations of the receptor tyrosine kinase c-kit or its ligand stem cell factor (SCF), which is encoded as a soluble and membrane-associated protein by the Steel gene in mice, lead to deficiencies of germ cells, melanocytes, and hematopoiesis, including the erythroid lineage. In the present study, we have used genetic methods to study the role of membrane or soluble presentation of SCF in hematopoiesis. Bone marrow–derived stromal cells expressing only a membrane-restricted (MR) isoform of SCF induced an elevated and sustained tyrosine phosphorylation of both c-kit and erythropoietin receptor (EPO-R) and significantly greater proliferation of an erythrocytic progenitor cell line compared with stromal cells expressing soluble SCF. Transgene expression of MR-SCF inSteel-dickie (Sld) mutants resulted in a significant improvement in the production of red blood cells, bone marrow hypoplasia, and runting. In contrast, overexpression of the full-length soluble form of SCF transgene had no effect on either red blood cell production or runting but corrected the myeloid progenitor cell deficiency seen in these mutants. These data provide the first evidence of differential functions of SCF isoforms in vivo and suggest an abnormal signaling mechanism as the cause of the severe anemia seen in mutants of the Sl gene.

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Signaling Through the Interaction of Membrane-Restricted Stem Cell Factor and c-kit Receptor Tyrosine Kinase: Genetic Evidence for a Differential Role in Erythropoiesis

Blood ◽

10.1182/blood.v91.3.879.879_879_889 ◽

1998 ◽

Vol 91 (3) ◽

pp. 879-889 ◽

Cited By ~ 2

Author(s):

Reuben Kapur ◽

Manus Majumdar ◽

Xiangli Xiao ◽

Monica McAndrews-Hill ◽

Karen Schindler ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Stromal Cells ◽

Stem Cell Factor ◽

Progenitor Cell ◽

Erythropoietin Receptor ◽

Soluble Form

Mutations of the receptor tyrosine kinase c-kit or its ligand stem cell factor (SCF), which is encoded as a soluble and membrane-associated protein by the Steel gene in mice, lead to deficiencies of germ cells, melanocytes, and hematopoiesis, including the erythroid lineage. In the present study, we have used genetic methods to study the role of membrane or soluble presentation of SCF in hematopoiesis. Bone marrow–derived stromal cells expressing only a membrane-restricted (MR) isoform of SCF induced an elevated and sustained tyrosine phosphorylation of both c-kit and erythropoietin receptor (EPO-R) and significantly greater proliferation of an erythrocytic progenitor cell line compared with stromal cells expressing soluble SCF. Transgene expression of MR-SCF inSteel-dickie (Sld) mutants resulted in a significant improvement in the production of red blood cells, bone marrow hypoplasia, and runting. In contrast, overexpression of the full-length soluble form of SCF transgene had no effect on either red blood cell production or runting but corrected the myeloid progenitor cell deficiency seen in these mutants. These data provide the first evidence of differential functions of SCF isoforms in vivo and suggest an abnormal signaling mechanism as the cause of the severe anemia seen in mutants of the Sl gene.

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The Essential Role of Stem Cell Factor/KIT Signaling in the Proliferation and Survival of Blast Cells from Transient Leukemia in Neonates with Down Syndrome.

Blood ◽

10.1182/blood.v112.11.1807.1807 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1807-1807

Author(s):

Tsutomu Toki ◽

Rika Kanezaki ◽

Souichi Adachi ◽

Hisanori Fujino ◽

Gang Xu ◽

...

Keyword(s):

Down Syndrome ◽

Stem Cell ◽

Tyrosine Kinase ◽

Stem Cell Factor ◽

Myeloid Leukemia ◽

Essential Role ◽

Therapeutic Benefits ◽

Significant Difference ◽

Transient Leukemia

Abstract Children with Down syndrome (DS) are predisposed to developing leukemia. A leukemoid reaction occurring uniquely in approximately 10% of newborn infants with DS referred to as transient leukemia (TL). This disorder, in most cases, resolves spontaneously within three months after birth. Of all TL patients approximately 20–30% develop myeloid leukemia (ML-DS) within four years. Although treatment with low dose cytarabine is effective in high-risk TL cases, about 20% of severe patients still suffer early death. Improved treatments for TL are necessary for a better long-term prognosis of DS patients. In this study, we demonstrate abundant KIT expression in all 13 TL patients examined, although no significant difference in expression levels was observed between TL and acute myeloid leukemia (AML). Stem cell factor (SCF) mRNA was expressed at extremely low levels in TL cells and there were no significant differences in SCF expression between TL and AML. SCF stimulated the proliferation of the TL cells from all five patients examined and treatment with the tyrosine kinase inhibitor imatinib suppressed the proliferation and KIT phosphorylation effectively in vitro. To investigate the signal cascade, we established the first SCF-dependent, ML-DS cell line, KPAM1. Withdrawal of SCF or treatment with imatinib induced apoptosis of KPAM1 cells. SCF activated the RAS/MAPK and PI3K/AKT pathways, followed by downregulation of the pro-apoptotic factor BIM and upregulation of the anti-apoptotic factor MCL1. Although we found novel missense mutations of KIT in two of 14 TL patients, functional analysis using KPAM1 cells showed that neither mutation led to KIT activation and neither reduced the cytotoxic effects of imatinib. These results suggest the essential role of SCF/KIT signaling in the proliferation of DS-related leukemia and the possibility of therapeutic benefits of KIT-targeting tyrosine kinase inhibitors for TL patients.

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Growth and bone health after hematopoietic stem cell transplantation or tyrosine kinase inhibitors in children with chronic myeloid leukemia: a single institution experience

Bone Abstracts ◽

10.1530/boneabs.2.p157 ◽

2013 ◽

Author(s):

Dilley Kimberley ◽

Broglie Larisa ◽

Chaudhury Sonali ◽

Hijiya Nobuko

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Tyrosine Kinase ◽

Bone Health ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Single Institution ◽

Hematopoietic Stem

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Clinical and prognostic significances of cancer stem cell markers in gastric cancer patients: a systematic review and meta-analysis

Cancer Cell International ◽

10.1186/s12935-021-01840-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Mahdieh Razmi ◽

Roya Ghods ◽

Somayeh Vafaei ◽

Maryam Sahlolbei ◽

Leili Saeednejad Zanjani ◽

...

Keyword(s):

Gastric Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Clinical Outcomes ◽

Cancer Progression ◽

Poor Prognosis ◽

Meta Analysis ◽

Disease Free Survival ◽

Stem Cell Markers ◽

Free Survival

Abstract Background Gastric cancer (GC) is considered one of the most lethal malignancies worldwide, which is accompanied by a poor prognosis. Although reports regarding the importance of cancer stem cell (CSC) markers in gastric cancer progression have rapidly developed over the last few decades, their clinicopathological and prognostic values in gastric cancer still remain inconclusive. Therefore, the current meta-analysis aimed to quantitatively re-evaluate the association of CSC markers expression, overall and individually, with GC patients’ clinical and survival outcomes. Methods Literature databases including PubMed, Scopus, ISI Web of Science, and Embase were searched to identify the eligible articles. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were recorded or calculated to determine the relationships between CSC markers expression positivity and overall survival (OS), disease-free survival (DFS)/relapse-free survival (RFS), disease-specific survival (DSS)/ cancer-specific survival (CSS), and clinicopathological features. Results We initially retrieved 4,425 articles, of which a total of 66 articles with 89 studies were considered as eligible for this meta-analysis, comprising of 11,274 GC patients. Overall data analyses indicated that the overexpression of CSC markers is associated with TNM stage (OR = 2.19, 95% CI 1.84–2.61, P = 0.013), lymph node metastasis (OR = 1.76, 95% CI 1.54–2.02, P < 0.001), worse OS (HR = 1.65, 95% CI 1.54–1.77, P < 0.001), poor CSS/DSS (HR = 1.69, 95% CI 1.33–2.15, P < 0.001), and unfavorable DFS/RFS (HR = 2.35, 95% CI 1.90–2.89, P < 0.001) in GC patients. However, CSC markers expression was found to be slightly linked to tumor differentiation (OR = 1.25, 95% CI 1.01–1.55, P = 0.035). Sub-analysis demonstrated a significant positive relationship between most of the individual markers, specially Gli-1, Oct-4, CD44, CD44V6, and CD133, and clinical outcomes as well as the reduced survival, whereas overexpression of Lgr-5, Nanog, and sonic hedgehog (Shh) was not found to be related to the majority of clinical outcomes in GC patients. Conclusion The expression of CSC markers is mostly associated with worse outcomes in patients with GC, both overall and individual. The detection of a combined panel of CSC markers might be appropriate as a prognostic stratification marker to predict tumor aggressiveness and poor prognosis in patients with GC, which probably results in identifying novel potential targets for therapeutic approaches.

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Downregulation of c-kit (Stem Cell Factor Receptor) in Transformed Hematopoietic Precursor Cells by Stroma Cells

Blood ◽

10.1182/blood.v93.2.554 ◽

1999 ◽

Vol 93 (2) ◽

pp. 554-563 ◽

Cited By ~ 5

Author(s):

Christoph Heberlein ◽

Jutta Friel ◽

Christine Laker ◽

Dorothee von Laer ◽

Ulla Bergholz ◽

...

Keyword(s):

Stem Cell ◽

Cell Line ◽

Stem Cell Factor ◽

Progenitor Cell ◽

Receptor Expression ◽

General Mechanism ◽

Ligand Interaction ◽

Kit Ligand ◽

Kit Receptor ◽

Progenitor Cell Line

Abstract We show a dramatic downregulation of the stem cell factor (SCF) receptor in different hematopoietic cell lines by murine stroma. Growth of the human erythroid/macrophage progenitor cell line TF-1 is dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3). However, TF-1 cells clone and proliferate equally well on stroma. Independent stroma-dependent TF-1 clones (TF-1S) were generated on MS-5 stroma. Growth of TF-1S and TF-1 cells on stroma still requires interaction between c-kit (SCF receptor) and its ligand SCF, because antibodies against c-kit inhibit growth to less than 2%. Surprisingly, c-kit receptor expression (RNA and protein) was downregulated by 2 to 3 orders of magnitude in TF-1S and TF-1 cells grown on stroma. This stroma-dependent regulation of the kit receptor in TF-1 was also observed on exposure to kit ligand-negative stroma, thus indicating the need for heterologous receptor ligand interaction. Removal of stroma induced upregulation by 2 to 4 orders of magnitude. Downregulation and upregulation of c-kit expression could also be shown for the megakaryocytic progenitor cell line M-07e and was comparable to that of TF-1, indicating that stroma-dependent regulation of c-kit is a general mechanism. Downregulation may be an economic way to compensate for the increased sensitivity of the c-kit/ligand interaction on stroma. The stroma-dependent c-kit regulation most likely occurs at the transcriptional level, because mechanisms, such as splicing, attenuation, differential promoter usage, or mRNA stability, could be excluded.

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Cooperation of Cancer Stem Cell Properties and Epithelial-Mesenchymal Transition in the Establishment of Breast Cancer Metastasis

Journal of Oncology ◽

10.1155/2011/591427 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 30

Author(s):

Tetsu Hayashida ◽

Hiromitsu Jinno ◽

Yuko Kitagawa ◽

Masaki Kitajima

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Metastatic Tumor ◽

Breast Cancer Metastasis ◽

Cell Junctions ◽

Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a multistep process in which cells acquire molecular alterations such as loss of cell-cell junctions and restructuring of the cytoskeleton. There is an increasing understanding that this process may promote breast cancer progression through promotion of invasive and metastatic tumor growth. Recent observations imply that there may be a cross-talk between EMT and cancer stem cell properties, leading to enhanced tumorigenicity and the capacity to generate heterogeneous tumor cell populations. Here, we review the experimental and clinical evidence for the involvement of EMT in cancer stem cell theory, focusing on the common characteristics of this phenomenon.

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