Effect of chemotherapy on cancer stem cells and tumor-associated macrophages in a prospective study of preoperative chemotherapy in soft tissue sarcoma

Keith M Skubitz, Jon D. Wilson, Edward Y Cheng, Bruce R. Lindgren, Kristin L Boylan, Amy P Skubitz

Research output: Contribution to journalReview article

Abstract

Background: Cancer stem cells (CSC) may respond to chemotherapy differently from other tumor cells. Methods: This study examined the expression of the putative cancer stem cell markers ALDH1, CD44, and CD133; the angiogenesis marker CD31; and the macrophage marker CD68 in soft tissue sarcomas (STS) before and after 4 cycles of chemotherapy with doxorubicin and ifosfamide in 31 patients with high-grade soft tissue sarcoma in a prospective clinical trial. Results: None of the markers clearly identified CSCs in STS samples. Macrophages represented a prominent component in viable tumor areas in pre-treatment STS biopsies, ranging from < 5 to > 50%. Furthermore, macrophages expressed CD44 and ALDH1. Macrophage density correlated with baseline maximum standardized uptake value (SUVmax) on fluoro-deoxyglucose positron emission tomography (PET) imaging. Pre-chemotherapy CD68 staining correlated positively with the baseline SUVmax, and negatively with the percent of viable tumor cells in post-chemotherapy resection samples. In particular, cases with more CD68-positive cells at biopsy had fewer viable tumor cells at resection, suggesting a better response to chemotherapy. Conclusions: In conclusion, ALDH1, CD44, and CD133 are not likely to be useful markers of CSCs in STS. However, our observation of infiltrating macrophages in STS specimens indicates that these immune cells may contribute significantly to STS biology and response to chemotherapy, and could provide a potential target of therapy. Future studies should investigate macrophage contribution to STS pathophysiology by cytokine signaling.

Original languageEnglish (US)
Article number130
JournalJournal of Translational Medicine
Volume17
Issue number1
DOIs
StatePublished - Apr 18 2019

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Chemotherapy
Neoplastic Stem Cells
Macrophages
Stem cells
Sarcoma
Tumors
Prospective Studies
Tissue
Drug Therapy
Neoplasms
Cells
Biopsy
Ifosfamide
Positron emission tomography
Deoxyglucose
Positron-Emission Tomography
Doxorubicin
Observation
Clinical Trials
Staining and Labeling

Keywords

  • Cancer stem cell
  • Chemotherapy
  • Macrophage
  • PET
  • Positron emission tomography
  • Sarcoma

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

@article{80d111e090fc48f799c1239c86740554,
title = "Effect of chemotherapy on cancer stem cells and tumor-associated macrophages in a prospective study of preoperative chemotherapy in soft tissue sarcoma",
abstract = "Background: Cancer stem cells (CSC) may respond to chemotherapy differently from other tumor cells. Methods: This study examined the expression of the putative cancer stem cell markers ALDH1, CD44, and CD133; the angiogenesis marker CD31; and the macrophage marker CD68 in soft tissue sarcomas (STS) before and after 4 cycles of chemotherapy with doxorubicin and ifosfamide in 31 patients with high-grade soft tissue sarcoma in a prospective clinical trial. Results: None of the markers clearly identified CSCs in STS samples. Macrophages represented a prominent component in viable tumor areas in pre-treatment STS biopsies, ranging from < 5 to > 50{\%}. Furthermore, macrophages expressed CD44 and ALDH1. Macrophage density correlated with baseline maximum standardized uptake value (SUVmax) on fluoro-deoxyglucose positron emission tomography (PET) imaging. Pre-chemotherapy CD68 staining correlated positively with the baseline SUVmax, and negatively with the percent of viable tumor cells in post-chemotherapy resection samples. In particular, cases with more CD68-positive cells at biopsy had fewer viable tumor cells at resection, suggesting a better response to chemotherapy. Conclusions: In conclusion, ALDH1, CD44, and CD133 are not likely to be useful markers of CSCs in STS. However, our observation of infiltrating macrophages in STS specimens indicates that these immune cells may contribute significantly to STS biology and response to chemotherapy, and could provide a potential target of therapy. Future studies should investigate macrophage contribution to STS pathophysiology by cytokine signaling.",
keywords = "Cancer stem cell, Chemotherapy, Macrophage, PET, Positron emission tomography, Sarcoma",
author = "Skubitz, {Keith M} and Wilson, {Jon D.} and Cheng, {Edward Y} and Lindgren, {Bruce R.} and Boylan, {Kristin L} and Skubitz, {Amy P}",
year = "2019",
month = "4",
day = "18",
doi = "10.1186/s12967-019-1883-6",
language = "English (US)",
volume = "17",
journal = "Journal of Translational Medicine",
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T1 - Effect of chemotherapy on cancer stem cells and tumor-associated macrophages in a prospective study of preoperative chemotherapy in soft tissue sarcoma

AU - Skubitz, Keith M

AU - Wilson, Jon D.

AU - Cheng, Edward Y

AU - Lindgren, Bruce R.

AU - Boylan, Kristin L

AU - Skubitz, Amy P

PY - 2019/4/18

Y1 - 2019/4/18

N2 - Background: Cancer stem cells (CSC) may respond to chemotherapy differently from other tumor cells. Methods: This study examined the expression of the putative cancer stem cell markers ALDH1, CD44, and CD133; the angiogenesis marker CD31; and the macrophage marker CD68 in soft tissue sarcomas (STS) before and after 4 cycles of chemotherapy with doxorubicin and ifosfamide in 31 patients with high-grade soft tissue sarcoma in a prospective clinical trial. Results: None of the markers clearly identified CSCs in STS samples. Macrophages represented a prominent component in viable tumor areas in pre-treatment STS biopsies, ranging from < 5 to > 50%. Furthermore, macrophages expressed CD44 and ALDH1. Macrophage density correlated with baseline maximum standardized uptake value (SUVmax) on fluoro-deoxyglucose positron emission tomography (PET) imaging. Pre-chemotherapy CD68 staining correlated positively with the baseline SUVmax, and negatively with the percent of viable tumor cells in post-chemotherapy resection samples. In particular, cases with more CD68-positive cells at biopsy had fewer viable tumor cells at resection, suggesting a better response to chemotherapy. Conclusions: In conclusion, ALDH1, CD44, and CD133 are not likely to be useful markers of CSCs in STS. However, our observation of infiltrating macrophages in STS specimens indicates that these immune cells may contribute significantly to STS biology and response to chemotherapy, and could provide a potential target of therapy. Future studies should investigate macrophage contribution to STS pathophysiology by cytokine signaling.

AB - Background: Cancer stem cells (CSC) may respond to chemotherapy differently from other tumor cells. Methods: This study examined the expression of the putative cancer stem cell markers ALDH1, CD44, and CD133; the angiogenesis marker CD31; and the macrophage marker CD68 in soft tissue sarcomas (STS) before and after 4 cycles of chemotherapy with doxorubicin and ifosfamide in 31 patients with high-grade soft tissue sarcoma in a prospective clinical trial. Results: None of the markers clearly identified CSCs in STS samples. Macrophages represented a prominent component in viable tumor areas in pre-treatment STS biopsies, ranging from < 5 to > 50%. Furthermore, macrophages expressed CD44 and ALDH1. Macrophage density correlated with baseline maximum standardized uptake value (SUVmax) on fluoro-deoxyglucose positron emission tomography (PET) imaging. Pre-chemotherapy CD68 staining correlated positively with the baseline SUVmax, and negatively with the percent of viable tumor cells in post-chemotherapy resection samples. In particular, cases with more CD68-positive cells at biopsy had fewer viable tumor cells at resection, suggesting a better response to chemotherapy. Conclusions: In conclusion, ALDH1, CD44, and CD133 are not likely to be useful markers of CSCs in STS. However, our observation of infiltrating macrophages in STS specimens indicates that these immune cells may contribute significantly to STS biology and response to chemotherapy, and could provide a potential target of therapy. Future studies should investigate macrophage contribution to STS pathophysiology by cytokine signaling.

KW - Cancer stem cell

KW - Chemotherapy

KW - Macrophage

KW - PET

KW - Positron emission tomography

KW - Sarcoma

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U2 - 10.1186/s12967-019-1883-6

DO - 10.1186/s12967-019-1883-6

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