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

Foster, Brittni M.; Zaidi, Danish; Young, Tyler R; Mobley, Mary E.; Kerr, Bethany A.

doi:10.3390/biomedicines6010031

Cited by 101 publications

(94 citation statements)

References 176 publications

(189 reference statements)

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“…CD117 expression and overactivation is found in several cancers including gastrointestinal stromal tumors (GIST), acute myeloid leukemia, and melanoma. [21], [24], [50]- [52] CD117 is best studied in GIST, which carries CD117 activating mutations. In GIST, CD117 expression and activation is associated with worse prognosis and bone metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…SCF, found in a dimer, binds to CD117 inducing dimerization, phosphorylation, and downstream signaling leading to proliferation, cytoskeletal rearrangement, and migration. [21], [41], [42] To examine how activation of the tyrosine kinase receptor CD117 may alter prostate cancer aggressiveness, we first examined phosphorylated (p-)CD117 levels in prostate cancer patients. The Harris 15 numbers of p-CD117+ cells per core increased with Gleason Score (Figure 5A).…”

Section: Scf Activation Of Cd117 Increases Prostate Cancer Progressionmentioning

confidence: 99%

“…Sunitinib targets several pathways and receptors including PDGFR and VEGFR in addition to CD117. [21], [43]- [45] Imatinib targets CD117, in addition to BCR-Abl, RET, and PDGFR. [43], [46] ISCK03 is a cell-permeable Harris 16 CD117 specific inhibitor that blocks SCF-induced phosphorylation.…”

Section: Cd117 Inhibition Prevents Prostate Cancer Progressionmentioning

confidence: 99%

“…[20] Additionally, CD117 is expressed on both normal stem cells and aggressive cancer cells with CD117 expression found on hematopoietic stem cells (HSCs) and stem cells in the murine prostate. [21]- [23] A single CD117 positive cell, which was also Lin-Sca-1+ CD133+ CD44+, regenerated an entire secreting prostate when mixed with urogenital mesenchymal cells and implanted in the renal capsule. Thus, this CD117 expressing cell was considered a prostate stem cell in adult tissue.…”

Section: Introductionmentioning

confidence: 99%

“…CD117 is a member of the type III tyrosine kinase receptors which play a key role in cell signaling and are responsible for maintaining cell functions such as cell survival, metabolism, cell growth and progression, proliferation, apoptosis, cell migration, and cell differentiation. [21],[24]- [26] These effects of CD117 activation and signaling support its potential role in prostate cancer progression and CSC maintenance. How CD117 activation alters proliferation, stemness, and migration remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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CD117/c-kit Defines a Prostate CSC-Like Subpopulation Driving Progression and TKI Resistance

Harris

Shi

Foster

et al. 2018

Preprint

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Cancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our prior study, CTCs in advanced prostate cancer patients were found to express CD117/ckit in a liquid biopsy. Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we show that CD117 expression in prostate cancer patients is associated with decreased overall and progression-free survival and that activation and phosphorylation of CD117 increases in prostate cancer patients with higher Gleason grades. To determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness, we used LNCaP-C4-2 and PC3-mm human prostate cancer cells, which contain a CD117+ subpopulation. We demonstrate that CD117+ cells display increased proliferation and migration. In prostaspheres, CD117 expression enhances sphere formation. In both 2D and 3D cultures, stemness marker gene expression is higher in CD117+ cells. Using xenograft limiting dilution assays and serial tumor initiation assays, we show that CD117+ cells represent a CSC population.Combined, these data indicate that CD117 expression potentially promotes tumor initiation and metastasis. Further, in cell lines, CD117 activation by SCF promotes faster proliferation and invasiveness, while blocking CD117 activation with tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.Harris 3

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Section: Discussionmentioning

confidence: 99%

Section: Scf Activation Of Cd117 Increases Prostate Cancer Progressionmentioning

confidence: 99%

Section: Cd117 Inhibition Prevents Prostate Cancer Progressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

CD117/c-kit Defines a Prostate CSC-Like Subpopulation Driving Progression and TKI Resistance

Harris

Shi

Foster

et al. 2018

Preprint

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A novel anti‐c‐Kit antibody–drug conjugate to treat wild‐type and activating‐mutant c‐Kit‐positive tumors

Kim

Baek

et al. 2021

Molecular Oncology

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c-Kit overexpression and activating mutations, which are reported in various cancers, including gastrointestinal stromal tumor (GIST), small-cell lung cancer (SCLC), acute myeloid leukemia, acral melanoma, and systemic mastocytosis (SM), confer resistance to tyrosine kinase inhibitors (TKIs). To overcome TKI resistance, an anti-c-Kit antibody-drug conjugate was developed in this study to treat wild-type and mutant c-Kitpositive cancers. NN2101, a fully human IgG1, was conjugated to DM1, a microtubule inhibitor, through N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) (to give NN2101-DM1). The antitumor activity of NN2101-DM1 was evaluated in vitro and in vivo using various cancer cell lines. NN2101-DM1 exhibited potent growth-inhibitory activities against c-Kit-positive cancer cell lines. In a mouse xenograft model, NN2101-DM1 exhibited potent growth-inhibitory activities against imatinib-resistant GIST and SM cells. In addition, NN2101-DM1 exhibited a significantly higher anti-cancer effect than carboplatin/etoposide against SCLC cells where c-Kit does not mediate cancer pathogenesis. Furthermore, the combination of NN2101-DM1 with imatinib in imatinib-sensitive GIST cells induced complete remission compared with treatment with NN2101-DM1 or imatinib alone in mouse xenograft models. These results suggest that NN2101-DM1 is a potential therapeutic agent for wild-type and mutant c-Kit-positive cancers.

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CD117‐Targeted Intraoperative Imaging of Gastrointestinal Stromal Tumor Using a Stem‐Cell‐Factor‐Labeled Fluorophore

Nomura,

Yokomizo,

Wang

et al. 2023

Advanced NanoBiomed Research

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Complete resection without damaging the capsule is the gold‐standard surgical approach for nonmetastatic gastrointestinal stromal tumors (GIST). However, accurately locating tumors during surgery is challenging because GIST is covered by normal mucosal tissue, leading to suboptimal surgeries and increased cancer recurrence rates. To enhance surgical care for GIST, a cutting‐edge near‐infrared (NIR) fluorescent nanoprobe is presented that enables real‐time navigation of GIST by specifically targeting CD117, a protein frequently overexpressed in GIST. By attaching a zwitterionic NIR fluorophore called ZW800‐1C to a CD117 ligand, stem cell factor (SCF), precise targeting is achieved while minimizing nonspecific tissue interactions. In in vitro studies, the high affinity of nanoprobe for CD117‐positive GIST‐T1 cell lines is demonstrated, while exhibiting no binding to CD117‐negative cells or GIST‐5 R cells. In a xenograft model of GIST‐T1 in mice, the nanoprobe produces strong and persistent NIR signals that last over 72 h following a single intravenous injection. Moreover, the nanoprobe successfully detects spontaneous tumors in the cecum of heterozygous Kit K641E mice. In these findings, the promise of CD117‐targeted molecular imaging is highlighted as an intraoperative strategy for GIST. Furthermore, this imaging approach holds potential for early diagnosis, as well as monitoring GIST prognosis before and after surgical resection.

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

Cited by 101 publications

References 176 publications

CD117/c-kit Defines a Prostate CSC-Like Subpopulation Driving Progression and TKI Resistance

CD117/c-kit Defines a Prostate CSC-Like Subpopulation Driving Progression and TKI Resistance

A novel anti‐c‐Kit antibody–drug conjugate to treat wild‐type and activating‐mutant c‐Kit‐positive tumors

CD117‐Targeted Intraoperative Imaging of Gastrointestinal Stromal Tumor Using a Stem‐Cell‐Factor‐Labeled Fluorophore

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