Prostate Cancer Stem Cell Markers Drive Progression, Therapeutic Resistance, and Bone Metastasis

Harris, Koran S.; Kerr, Bethany A.

doi:10.1155/2017/8629234

Cited by 88 publications

(98 citation statements)

References 100 publications

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“…In our study, we utilized the markers CXCR4 and CD117 to examine the numbers of circulating progenitor cells in the bloodstream. These two receptors are classic markers of cells residing in the bone marrow but are also postulated to be expressed on circulating tumor cells [30,46]. Using a syngeneic model, we are unable to determine the origin of these cells definitively, but their numbers are indicative of pre-metastatic niche formation and progression of cancers toward a more aggressive phenotype which is being driven by platelet-sequestered proteins.…”

Section: Discussionmentioning

confidence: 99%

Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

Kerr

Harris

Shi

et al. 2020

Preprint

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The development of distant metastasis is the main cause of prostate cancer (CaP)related death with the skeleton being the primary site of metastasis. While the progression of primary tumors and the growth of bone metastatic tumors are well described, the mechanisms controlling pre-metastatic niche formation and homing of CaP to bone remain unclear. Through prior studies, we demonstrated that platelet secretion was required for ongoing tumor growth and pre-metastatic tumor-induce bone formation and bone marrow-derived cell mobilization to cancers supporting angiogenesis. We hypothesized that proteins released by the platelet α granules were responsible for inducing changes in the pre-metastatic bone niche. We found that the classically antiangiogenic protein thrombospondin (TSP)-1 was significantly increased in the platelets of mice bearing tumors. To determine the role of increased TSP-1, we implanted tumors in TSP-1 null animals and assessed changes in tumor growth and pre-metastatic niche formation. TSP-1 loss resulted in increased tumor size and enhanced angiogenesis but reduced bone marrow-derived cell mobilization and tumor-induced bone formation with enhanced osteoclast formation. We hypothesized that these changes in the pre-metastatic niche were due to the retention of TGF-β1 in the platelets of mice with TSP-1 deleted. To assess the importance of platelet-derived TGF-β1, we implanted CaP tumors in mice with platelet-specific deletion of TGF-β1. Similar to TSP-1 deletion, loss of platelet TGF-β1 resulted in increased angiogenesis with a milder effect on tumor size and BMDC release.Within the bone microenvironment, platelet TGF-β1 deletion prevented tumor-induced bone formation due to increased osteoclastogenesis. Thus, we demonstrate that the TSP-1/TGF-β1 axis regulates pre-metastatic niche formation and tumor-induced bone Kerr 3 turnover. Targeting the platelet release of TSP-1 or TGF-β1 represents a potential method to interfere with the process of CaP metastasis to bone. Abbreviations: CaP: prostate cancer; MMP: matrix metalloproteinase; RANKL: receptor activator of NF-κB ligand; SMA: smooth muscle actin; TGF-β1: transforming growth factor beta-1 TRAP: tartrate-resistant acid phosphatase; TSP: thrombospondin, VEGF: vascular endothelial growth factor Kerr 4 INTRODUCTION An estimated 191,930 men will be diagnosed with prostate cancer (CaP) in 2020, surpassing even lung cancer in incidence [1]. Early detection has improved survival rates to 100 percent with a local diagnosis. However, men diagnosed with distant CaP metastases face a 30 percent chance of survival at five years, with bone being the most common site of CaP metastasis [1]. In fact, 90% of CaP patients display skeletal metastases at autopsy regardless of prior bone symptom reporting. Bone metastases are responsible for severe bone pain, decreased mobility, fractures, spinal cord compression, and hypercalcemia resulting in patient morbidity. Metastatic skeletal CaP lesions can produce many growth factors and cytokines which alter the bone struc...

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Section: Discussionmentioning

confidence: 99%

Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

Kerr

Harris

Shi

et al. 2020

Preprint

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“…[11]- [18] Several markers for CTCs and CSCs are postulated in the literature. [7] In a prior study, we identified CD117/c-kit positive CTCs in prostate cancer patients that were associated with cancer severity and biochemical recurrence. [19] CD117+ cell numbers were increased in the prostate tissue and circulation of patients with Gleason 8+ disease.…”

Section: Introductionmentioning

confidence: 96%

“…[3], [5], [6] However, <0.01% of these cells will initiate metastases. [3], [5] While multiple markers were proposed for prostate cancer CTCs, [7] most have yet to be validated in the circulation of patients. Further, it remains unproven whether CTCs can initiate metastases, which is partially due to an inability to examine the journey of CTCs from the primary tumor to the metastatic niche.…”

Section: Introductionmentioning

confidence: 99%

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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“…being a bona fide CSC marker for prostate and pancreatic cancers [44,45], evidently support its presence to promote therapy resistance. Also, studies in AML and NSCLC showed the presence of CXCR4 has a positive correlation with therapy resistance though they consider ligand-mediated signals as a responsible reason for the same [46,47].…”

Section: Discussionmentioning

confidence: 79%

CXCR4 intracellular protein regulates drug resistance and tumorigenic potential via modulating the expression of Death Receptor 5

Nengroo

Maheshwari

Singh

et al. 2019

Preprint

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CXCR4 overexpression in solid tumors has been strongly associated with poor prognosis and adverse clinical outcome. However, CXCR4 signaling inhibitor drug Plerixafor has shown limited clinical success in cancer treatment. Therefore, CXCR4 signaling may not be the exclusive contributor to its pro-tumorigenic functions. In our continuous effort to understand the chemokine receptor signaling inhibition as cancer therapy, here we unexpectedly discovered that instead of its signaling, intracellular CXCR4 protein augments therapy resistance and pro-tumorigenic functions. Unbiased proteome profiler apoptosis array followed by immunoblot, FACS, real-time PCR and ChIP analyses demonstrate that CXCR4 promotes DR5 downregulation via modulating differential recruitment of transcription factors p53 and YY1 to its promoter. Surprisingly, inhibiting CXCR4 mediated signals failed to block the above phenotype. Irrespective of CXCR4 surface expression, its loss compromised colon tumor growth in vivo. Finally, TCGA data mining and human patient sample data analysis showed CXCR4 and DR5 are inversely regulated in human cancers. Together, we showed evidence for the first time that targeting CXCR4 intracellular protein may be critical to dampen the pro-tumorigenic functions of CXCR4. explain the pro-tumorigenic functions of these axes. In our relentless effort to understand the chemokine receptor signaling inhibition in cancer therapy [15,[19][20][21][22], here we surprisingly discovered that neither CXCR7 nor CXCR4-CXCL12 signaling axis is responsible for therapy resistance and tumorigenic potential, rather CXCR4 protein in the cancer cells plays a very critical role in positively modulating pro-tumorigenic functions such as therapy resistance across multiple solid tumors. Our intricate in vitro and in vivo experiments in multiple cancer settings for CXCR4 gain and loss of function studies demonstrate that CXCR4 protein but not its CXCL12 mediated signals modulate chemotherapy resistance and tumorigenic potential via inversely regulating the expression of DR5. CXCR4-DR5 inverse regulation was also validated in diverse human cell lines and human cancer patient samples, suggesting its possible therapeutic implications.

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Prostate Cancer Stem Cell Markers Drive Progression, Therapeutic Resistance, and Bone Metastasis

Cited by 88 publications

References 100 publications

Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

Platelet TSP-1 Controls Prostate Cancer-Induced Osteoclast Differentiation and Bone Marrow-Derived Cell Mobilization through TGFβ-1

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

CXCR4 intracellular protein regulates drug resistance and tumorigenic potential via modulating the expression of Death Receptor 5

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