Abstract
Simple SummaryThis study aimed to prove the early presence of circulating tumor cells (CTCs) with viability and tumorigenesis in a murine model that spontaneously develops breast cancer. Serial CTC examinations were performed on NeuN transgenic mice, starting from the age of 8 weeks and continuing after palpable tumor formation. Prior to the detection of palpable tumors, the CTC counts rose over time from 1 ± 1.6 to 16 ± 9.5 per 75 μL; this number continued to grow with tumor development. The viability and tumorigenesis of the collected CTCs were confirmed by re-implanting the cells into a non-cancer-bearing mouse. Ultrasonography with Doppler showed a significant correlation between CTCs and tumor vascular density (p-value < 0.01), rather than tumor volume (p-value 0.076).Background: This study used NeuN transgenic (NTTg) mice with spontaneous breast tumor development to evaluate the dynamic changes of circulating tumor cells (CTCs) prior to and during tumor development. Methods: In this longitudinal, clinically uninterrupted study, we collected 75 μL of peripheral blood at the age of 8, 12, 16, and 20 weeks in the first group of five mice, and at the age of 32 weeks, the time of tumor palpability, and one week after tumor palpability in the second group of four mice. Diluted blood samples were run through a modified mouse-CMx chip to isolate the CTCs. Results: The CTC counts of the first group of mice were low (1 ± 1.6) initially. The average CTC counts were 16 ± 9.5, 29.0 ± 18.2, and 70.0 ± 30.3 cells per 75 μL blood at the age of 32 weeks, the time of tumor palpability, and one week after tumor palpability, respectively. There was a significant positive correlation between an increase in CTC levels and tumor vascular density (p-value < 0.01). This correlation was stronger than that between CTC levels and tumor size (p-value = 0.076). The captured CTCs were implanted into a non-tumor-bearing NTTg mouse for xenografting, confirming their viability and tumorigenesis. Conclusion: Serial CTCs during an early stage of tumor progression were quantified and found to be positively correlated with the later tumor vascular density and size. Furthermore, the successful generation of CTC-derived xenografts indicates the tumorigenicity of this early onset CTC population.
Highlights
Cancer cells detaching from the primary tumor site into circulation and being transported as circulating tumor cells (CTCs) to the distal organs comprise the initial step of metastasis
Despite the correlation between the increase in the CTC count and the increase in either vascularity or tumor size in the respective individuals, we found that the CTC count did not correlate with tumor volume absolutely, meaning that we cannot predict the actual tumor volume of any individual based solely on their CTC count
Our results showed that CTC counts are more strongly correlated with tumor vascularity than tumor size (p < 0.01 for vascular density versus p = 0.076 for tumor size)
Summary
Cancer cells detaching from the primary tumor site into circulation and being transported as circulating tumor cells (CTCs) to the distal organs comprise the initial step of metastasis. DTCs in bone marrow indicate that CTCs came from a primary tumor and settled in the bone marrow [3]. This finding implies that CTCs are present in patients with early-stage cancers. There was a significant positive correlation between an increase in CTC levels and tumor vascular density (p-value < 0.01). This correlation was stronger than that between CTC levels and tumor size (p-value = 0.076). Conclusion: Serial CTCs during an early stage of tumor progression were quantified and found to be positively correlated with the later tumor vascular density and size. The successful generation of CTC-derived xenografts indicates the tumorigenicity of this early onset CTC population
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