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Table 2. Examples of experimental systems to study miRNA content in liquid biopsy
Experimental mouse system miRNA studied Major results obtained Ref.
Mouse models of prostate cancer miR-141-3p MicroRNAs derived from human prostate cancer [52]
xenografted with 22Rv1 human xenografts are readily measured in plasma of mouse
prostate cancer- derived cells models allowing a clear distinction between tumor-
xenografted mice and controls
Transgenic mouse model of miR-141-3p miR-375 miR- Global miRNA profiling allows to identified a set of ten [54]
prostate cancer 298 miR-346 miRNAs significantly altered in serum of transgenic mice
compared to healthy controls
Mice bearing colorectal carcinoma miR-141-3p miR-221-3p Evidences of gateways regulating the levels of circulating [55]
cell lines xenografts miR-222-3p miRNA
Mouse models bearing human miR-95 miR-141-3p miR- A panel of 10 miRNAs are dysregulated in tumor bearing [56]
small cell lung cancer (SCLC) 200a-3p miR-200b-3p mouse models. The same miRNAs were also confirmed to
tumor xenografts miR-200c-3p miR-210- be altered in stage dependent manner in plasma isolated
3p miR-335-3p miR-375 from SCLC patients
miR-429
Mouse models of breast cancer miR-10b-5p miR-195-5p A complex miRNA dysregulation in the circulation athymic [70]
xenografted with MDA-MB-231 miR-497-5p miR-221-3p nude xenografted mice was detected compared to tumor-
cells free controls
Foxp3 heterozygous Scurfy miR-200c-3p miR-141-3p Despite levels of miR-200c and miR-141 were found to [71]
mutant (Foxp3 sf/+ ) female mice. be lower in Foxp3 sf/+ tumor cells than in normal breast
The loss of Foxp3 expression, due epithelial cells, plasma levels of miR- 200c and miR-141 in
to the frameshift mutation leads the Foxp3 sf/+ mice increased during tumor progression
to the spontaneous development and metastasis
of breast cancer and lung
metastases.

miRNAs at significantly altered levels in the serum of mice with advanced prostate cancer compared to
healthy mice used as controls. Interestingly, four miRNAs altered in mice (mmu-miR-141, mmu-miR-298,
mmu-miR-346 and mmu-miR-375) were also found to be expressed at higher levels in the serum of patients
with metastatic prostate cancer compared with control subjects. Moreover, three of these (hsa-miR-141,
hsa-miR-298 and hsa-miR-375) were upregulated in prostate tumors compared with normal prostate tissue,
suggesting that they are directly released from the tumor into the blood as disease progresses. This study was
the first to demonstrate that specific serum miRNAs (miR-141, miR-298 and miR-375) are common between
human prostate cancer and a mouse model of the disease, highlighting the potential of such models for the
discovery of novel biomarkers.

Zhang et al. investigated FOXP3-inducible breast cancer cells, Foxp3 heterozygous Scurfy mutant (Foxp3
[71]
sf/+) female mice, and patients with breast cancer for characterization of the formation and regulation of the
miR-200 family in breast cancer cells and circulation. While levels of miR-200c and miR-141 were lower in
Foxp3 sf/+ tumor cells than in normal breast epithelial cells, plasma levels of miR-200c and miR-141 in the
Foxp3 sf/+ mice increased during tumor progression and metastasis. Interestingly, the levels of miR-200c
and miR-141 were higher in plasma from patients with metastatic breast cancer than in plasma from those
with localized breast cancer, with benign breast tumors, with a family history of breast cancer, or from
healthy controls. The conclusion of the work reported by Zhang et al. supports the concept that miR-200c
[71]
and miR-141 are regulated by a FOXP3-KAT2B axis in breast cancer cells, and circulating levels of miR-200c
and miR-141 are potential biomarkers for early detection of breast cancer metastasis. Moreover, they highlight
the idea that roadblocks evolve during the natural history of tumors.

LIQUID BIOPSY IN MICE BEARING COLORECTAL CARCINOMA XENOGRAFTS OBTAINED
AFTER IMPLANTATION OF HT-29 AND LOVO CARCINOMA CELLS
Analysis of miRNA content has been recently performed in mice xenografted with colon cancer cell lines .
[55]
Among the different xenografted models the one based on the implantation of the HT-29 and LoVo CRC