A unique gene signature distinguishes circulating tumor cells (CTCs) associated with breast cancer brain metastasis (BCBM) from primary breast cancer cells, researchers report.
“The application of CTC tests in the clinic can serve as a sensitive screening method for the detection of nascent brain micrometastatic disease, potentially complementing MRI, particularly in cases where MRI shows no evidence of overt BCBM,” Dr. Dario Marchetti from Houston Methodist Research Institute, Houston, Texas, told Reuters Health by email.
Using a 3-step workflow, Dr. Marchetti’s team identified a distinct population of CTCs in breast cancer patients that differed from cells in healthy female controls.
CTCs from women with advanced disease differed from 31 primary breast cancer samples, with 29,758 genes downregulated and 1,972 upregulated, indicative of generalized low CTC transcriptional activity, according to the August 4 Nature Communications online report.
“BCBM patients had twice as much Ki67High CTCs, while No-BCBM patients had 60% greater Ki67Low CTCs,” Dr. Marchetti said. “We find fascinating that the detection of one single CTC marker like Ki67 can act as a discriminatory indicator for the potential of BCBM onset.”
Further analysis identified a unique 126-gene signature that significantly distinguished BCBM patients from No-BCBM patients.
This signature was associated with upregulation of Notch activity, activation of cellular functional annotations associated with distant metastases, and an increase of pro-inflammatory chemokines, immunomodulatory networks, and mitogenic growth factors.
Moreover, the signature shared no features of the 51-gene signature that distinguished estrogen receptor (ER)-positive from ER-negative disease.
“In the present study, we not only confirmed that CTCs associated with clinical BCBM have higher activation of Notch signaling, in line with previous findings from our lab, but also expanded upon these discoveries,” the researchers note. “We discovered novel inflammatory and immunomodulatory networks that may play vital roles in CTC-driven immune evasion and mitotic reactivation. The relevance of these signaling mechanisms in terms of cancer dormancy and development of brain metastases need to be confirmed by future validation studies.”
“The extension and/or application of these CTC discoveries may foster the development of CTC tests applicable in the clinic to: 1) detect BCBM in its early stage, 2) formulate rational therapies targeted specifically to BCBM, 3) evaluate efficacy of these therapies in real-time and over time (longitudinal monitoring),” Dr. Marchetti said by email.
Dr. Adrian Wiegmans from QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia, who recently reviewed methods for identifying CTC populations, told Reuters Health by email, “CTC have to be robust to survive dissociation from the main tumor mass, traveling in the circulation to arrive at the secondary site, in this case the brain. It is interesting that there is overwhelming silencing of transcription in CTCs, with 93.4% of genes that changed were down regulated, supporting the fields hypothesis that to be robust CTC are metabolically more dormant and resistant to cell-death signaling.”
“Secondly, strong evidence defining a quiescent state in CTCs has implications for therapeutically targeting CTCs, as most chemotherapies rely upon the differential between the proliferation observed in oncogenic versus normal cells,” he said.
“It's very hard to treat metastases,” Dr. Wiegmans added. “CTCs represent the seeding capacity of a secondary tumor and, based on how they establish mitotic reactivation under cues from a foreign microenvironment, the resulting metastasis is essentially a different cancer.”
Nat Commun 2017.