Abstract
Simple SummaryMetastasis is the leading cause of death in breast cancer, and it can be predicted by the detection of circulating tumor cells in the blood and disseminated tumor cells in the bone marrow, which are usually detected by epithelial marker proteins. However, tumor cells with mesenchymal attributes down-regulate the expression of epithelial marker proteins, and are therefore difficult to detect. Here, we found that the protein-cysteine–rich angiogenetic inducer 61 (Cyr61) is strongly expressed in tumor cells with mesenchymal attributes. Cyr61 expression was undetectable in normal blood cells, suggesting that Cyr61 might represent a tumor-associated protein. Functional experiments showed that the loss of Cyr61 reduces the viability of breast tumor cells. Thus, Cyr61 might represent an interesting anti-metastatic target that needs to be explored in future studies.(1) Background: the early detection of cancer cells in the blood or bone marrow of breast cancer patients improves the understanding of metastasis. Disseminating tumor cells in the bone marrow with a pronounced manifestation of mesenchymal markers (mDTC) are difficult to detect by epithelial markers, but they are relevant in the initiation of metastasis. (2) Methods: the breast cancer mDTC cell line BC-M1 was analyzed by mass spectrometry, which revealed high levels of the protein-cysteine–rich angiogenic inducer 61 (Cyr61). The function of Cyr61 was investigated using shRNA and hypoxia. Peripheral blood samples from 35 breast cancer patients were investigated for CTCs defined as cytokeratin-positive/CD45-negative cells. (3) Results: the Cyr61 levels are elevated in mDTC lines from breast, lung, and prostate cancer patients. The loss of Cyr61 resulted in the diminished expression of hypoxia-inducible factor 1-alpha, and increased apoptosis. Cyr61 was present in 47 (43%) of the 109 detected circulating tumor cells (CTCs), while the blood and bone marrow cells from healthy controls were Cyr61-negative. (4) Conclusions: Cyr61 is expressed in mDTC lines, supports the viability of cancer cells, and classifies a new subset of cytokeratin-positive CTCs, which deserves further investigation.
Highlights
The ‘liquid biopsy’ analysis of the peripheral blood of cancer patients has made remarkable progress [1]
We confirmed the levels of cysteine–rich angiogenic inducer 61 (Cyr61) by Western blot analysis, and observed that the cell lines with mesenchymal attributes or an intermediate epithelial/mesenchymal phenotype were positive for Cyr61 (Figure 1C, Figure S1)
Due to the remarkably-high levels of these integrins in the analysed cell lines, we investigated whether the dissemination of tumor cells to the bone marrow might affect the levels of integrin αv and integrin β3
Summary
The ‘liquid biopsy’ analysis of the peripheral blood of cancer patients has made remarkable progress [1]. The subjects of liquid biopsy are circulating tumor cells (CTCs) or molecules like nucleic acids or proteins that are released by tumor cells into the blood. When such tumor-derived biomaterial is detected in the blood, it can be used for the early detection of cancer, the prediction of metastatic relapse, or therapy monitoring [2]. The detection of CTCs in the blood, and their relatives that have already reached secondary sites—the disseminated tumor cells in the bone marrow (DTCs)— are useful markers for the prediction of distant metastasis [3]. There is an urgent need for new markers that support the detection of mDTCs and mCTCs in routine analysis
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