CD117⁺ cells in the circulation are predictive of advanced prostate cancer.

Bethany A Kerr,Warren D Heston,Tatiana V Byzova,Joseph C Klink,Ranko Miocinovic,Maria C Mir,Armine K Smith,Donna E Hansel,Andrew J Stephenson,Tiffany Sturey,Eric A Klein,Katherine E Watts,Xiaoxia Z West,Amanda W Alzayed

doi:10.18632/oncotarget.2796

Abstract

Circulating tumor cells (CTCs) are associated with cancer progression, aggressiveness and metastasis. However, the frequency and predictive value of CTCs in patients remains unknown. If circulating cells are involved in tumor aggressiveness and metastasis, then cell levels should decline upon tumor removal in localized cancer patients, but remain high in metastatic patients. Accordingly, proposed biomarkers CD117/c-kit, CD133, CXCR4/CD184, and CD34-positive cell percentages in the blood of patients undergoing radical prostatectomy for localized cancer were assessed by flow cytometry prior to intervention and 1-3 months postoperatively. Only circulating CD117⁺ cell percentages decreased after radical prostatectomy, increased with cancer progression and correlated with high PSA values. Notably, postoperative CD117⁺ levels did not decrease in patients experiencing biochemical recurrence. In a xenograft model, CD117-enriched tumors were more vascularized and aggressive. Thus, CD117 expression on CTCs promotes tumor progression and could be a biomarker for prostate cancer diagnosis, prognosis, and/or response to therapy.

Highlights

IntroductionProposed markers distinguishing prostate cancer from benign tissues include: CD117, CD133, CXCR4, and CD34. [1,2,3] CD133/prominin-1 and CD117/ c-kit were documented in multiple solid neoplasms, [2,3,4,5,6] where immunohistological staining of these markers correlated with aggressive tumors and increased resistance to chemotherapy and radiotherapy. [5] Prostate cancers express CXCR4/CD184, which stimulates metastasis towards the bone microenvironment. [1, 7] CD34+ cells, hematopoietic progenitors recruited to tumors to support their growth, [8, 9] correlate with primary prostate cancer progression. [10] While, these markers show promise in murine models, on cancer cell lines, and in primary tumor staining, they were not examined in the circulation of patients or linked to tumor presence
If circulating cells are involved in tumor aggressiveness and metastasis, cell levels should decline upon tumor removal in localized cancer patients, but remain high in metastatic patients
Several cell surface markers, including CD133, CD117, CD34 and CXCR4 were proposed to reflect the presence and/or severity of tumors. To establish whether these markers are predictive for human cancers, numbers of CD133+, CD117+, CD34+, or CXCR4+ circulating cells were assessed in prostate cancer patients before and after prostatectomy

Summary

Introduction

Proposed markers distinguishing prostate cancer from benign tissues include: CD117, CD133, CXCR4, and CD34. [1,2,3] CD133/prominin-1 and CD117/ c-kit were documented in multiple solid neoplasms, [2,3,4,5,6] where immunohistological staining of these markers correlated with aggressive tumors and increased resistance to chemotherapy and radiotherapy. [5] Prostate cancers express CXCR4/CD184, which stimulates metastasis towards the bone microenvironment. [1, 7] CD34+ cells, hematopoietic progenitors recruited to tumors to support their growth, [8, 9] correlate with primary prostate cancer progression. [10] While, these markers show promise in murine models, on cancer cell lines, and in primary tumor staining, they were not examined in the circulation of patients or linked to tumor presence. [1, 7] CD34+ cells, hematopoietic progenitors recruited to tumors to support their growth, [8, 9] correlate with primary prostate cancer progression. The recommended screening test for prostate cancer: prostate specific antigen (PSA) is mired in controversy surrounding its benefits and its ability to guide www.impactjournals.com/oncotarget appropriate treatment options for patients with newlydiagnosed, localized prostate cancer. This is due to the favorable natural history of low-grade prostate cancer, and to diagnostic imperfections in PSA and prostate biopsies. A PSA-based screening study demonstrated a 20% reduction of prostate cancer-specific death. [12] this required screening 1410 men and treating 48 additional cases to prevent one death. [12] These findings suggested high rates of over-diagnosis and overtreatment of clinically insignificant prostate cancer and stressed the need to develop new markers to effectively identify men at risk of dying from prostate cancer

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