TY - JOUR
T1 - Micronuclei in Circulating Tumor Associated Macrophages Predicts Progression in Advanced Colorectal Cancer
AU - Kasabwala, Dimpal M.
AU - Bergan, Raymond C.
AU - Gardner, Kirby P.
AU - Lapidus, Rena
AU - Tsai, Susan
AU - Aldakkak, Mohammed
AU - Adams, Daniel L.
N1 - Funding Information:
This manuscript was supported by the U.S. Army Research Office (ARO) and the Defense Advanced Research Projects Agency (DARPA) (W911NF-14-C-0098). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government. Publication Fees for this manuscript were paid for by Creatv MicroTech, Inc.
Publisher Copyright:
© 2022 by the authors.
PY - 2022/11
Y1 - 2022/11
N2 - Micronuclei (MN) are fragments of damaged nucleic acids which budded from a cell’s nuclei as a repair mechanism for chromosomal instabilities, which within circulating white blood cells (cWBCs) signifies increased cancer risk, and in tumor cells indicates aggressive subtypes. MN form overtime and with therapy induction, which requires sequential monitoring of rarer cell subpopulations. We evaluated the peripheral blood (7.5 mL) for MN in Circulating Stromal Cells (CStCs) in a prospective pilot study of advanced colorectal cancer patients (n = 25), identifying MN by DAPI+ structures (<3 µm) within the cellular cytoplasm. MN+ was compared to genotoxic induction, progression free survival (PFS) or overall survival (OS) hazard ratios (HR) over three years. MN were identified in 44% (n = 11/25) of CStCs, but were not associated with genotoxic therapies (p = 0.110) nor stage (p = 0.137). However, presence of MN in CStCs was independently prognostic for PFS (HR = 17.2, 95% CI 3.6–80.9, p = 0.001) and OS (HR = 70.3, 95% CI 6.6–752.8, p = 0.002), indicating a non-interventional mechanism in their formation. Additionally, MN formation did not appear associated with chemotherapy induction, but was correlated with tumor response. MN formation in colorectal cancer is an underlying biological mechanism that appears independent of chemotherapeutic genotoxins, changes during treatment, and predicts for poor clinical outcomes.
AB - Micronuclei (MN) are fragments of damaged nucleic acids which budded from a cell’s nuclei as a repair mechanism for chromosomal instabilities, which within circulating white blood cells (cWBCs) signifies increased cancer risk, and in tumor cells indicates aggressive subtypes. MN form overtime and with therapy induction, which requires sequential monitoring of rarer cell subpopulations. We evaluated the peripheral blood (7.5 mL) for MN in Circulating Stromal Cells (CStCs) in a prospective pilot study of advanced colorectal cancer patients (n = 25), identifying MN by DAPI+ structures (<3 µm) within the cellular cytoplasm. MN+ was compared to genotoxic induction, progression free survival (PFS) or overall survival (OS) hazard ratios (HR) over three years. MN were identified in 44% (n = 11/25) of CStCs, but were not associated with genotoxic therapies (p = 0.110) nor stage (p = 0.137). However, presence of MN in CStCs was independently prognostic for PFS (HR = 17.2, 95% CI 3.6–80.9, p = 0.001) and OS (HR = 70.3, 95% CI 6.6–752.8, p = 0.002), indicating a non-interventional mechanism in their formation. Additionally, MN formation did not appear associated with chemotherapy induction, but was correlated with tumor response. MN formation in colorectal cancer is an underlying biological mechanism that appears independent of chemotherapeutic genotoxins, changes during treatment, and predicts for poor clinical outcomes.
KW - advanced colorectal cancer
KW - cancer associated macrophage like cells (CAMLs)
KW - circulating stromal cells (CStCs)
KW - DNA damage
KW - genotoxins
KW - liquid biopsy
KW - micronuclei (MN)
KW - molecular stress
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U2 - 10.3390/biomedicines10112898
DO - 10.3390/biomedicines10112898
M3 - Article
C2 - 36428466
AN - SCOPUS:85149480012
SN - 2227-9059
VL - 10
JO - Biomedicines
JF - Biomedicines
IS - 11
M1 - 2898
ER -