Abstract:We reported on the ability of immortalized or oncosuppressor-mutated cells (OMCs) to uptake circulating cancer-factors and give tumors when transplanted into mice. This led to the first biological based liquid biopsy test, which we called MATER-D platform. In the present study, we showed for the first time that a different type of OMCs (PTEN-deficient human epithelial MCF10A cells) turn malignant when exposed to cancer patient’s sera, confirming the concept that different cells with diverse oncosuppressor muta… Show more
“…9). As we already hypothesized and proved in vitro [43], this finding suggests that cancer EVs may have targeted two different cell populations and induced their independent transformation. These data bring more evidence that circulating EVs shed by cancer cells possess the ability to transform target cells at distance even in vivo and strengthens our hypothesis that the malignant transformation of uptaking cells might not be due solely to the messages carried by the cancer EVs but it is also determined by the type of cells that uptake, transcribe and translate the onco-message (mesenchymal vs epithelial cells).Fig.…”
Section: Resultssupporting
confidence: 65%
“…The coexistence of two different cancers in the lungs of the mice injected with cancer EVs seems to support the concept that the phenotype expressed by the transforming cells might have limitations dictated by the nature of the target cell rather than the type of onco-message, as we recently demonstrated in vitro [43].…”
Background
We reported that horizontal transfer of malignant traits to target cells is a potential pathway to explain cancer dissemination. Although these results were encouraging, they were never corroborated by data showing the molecular mechanisms responsible for the observed phenomenon.
Methods
In the present study, we exposed
BRCA1
-KO fibroblasts to extracellular vesicles (EVs) isolated from a colon cancer cell line (HT29) and from sera of patients with colorectal cancer. Three weeks after exposure, fibroblasts were injected subcutaneously into NOD-SCID mice. Whole genome sequencing, transcriptome analysis and RNA sequencing of cancer EVs and fibroblasts prior and after exposure to cancer EVs were performed.
Results
Phenotypical transformation of the fibroblasts into colon cancer cells was confirmed by histopathological study of the xenotransplants. We observed that EV-mediated transfer of cancer microRNAs was responsible for the transition from a mesenchymal to an epithelial phenotype (MET) in the treated fibroblasts as well as activation of cell cycle progression and cell survival pathways. DNA and RNA sequencing suggested that cancer DNA was transferred and possibly transcribed in target cells. Furthermore, injection of colon cancer EVs in the tail vein of NOD-SCID mice determined neoplastic transformation and metastases in the lungs of the mice confirming for the first time the hypothesis that transfer of malignant epithelial cancer traits to distant target cells is a concept applicable to in vivo models.
Conclusions
These discoveries shed new light into the molecular mechanisms behind the horizontal transfer of malignant traits and confirm the notion that metastatic disease might be reproduced through transfer of circulating genetic material.
Electronic supplementary material
The online version of this article (10.1186/s13046-019-1248-2) contains supplementary material, which is available to authorized users.
“…9). As we already hypothesized and proved in vitro [43], this finding suggests that cancer EVs may have targeted two different cell populations and induced their independent transformation. These data bring more evidence that circulating EVs shed by cancer cells possess the ability to transform target cells at distance even in vivo and strengthens our hypothesis that the malignant transformation of uptaking cells might not be due solely to the messages carried by the cancer EVs but it is also determined by the type of cells that uptake, transcribe and translate the onco-message (mesenchymal vs epithelial cells).Fig.…”
Section: Resultssupporting
confidence: 65%
“…The coexistence of two different cancers in the lungs of the mice injected with cancer EVs seems to support the concept that the phenotype expressed by the transforming cells might have limitations dictated by the nature of the target cell rather than the type of onco-message, as we recently demonstrated in vitro [43].…”
Background
We reported that horizontal transfer of malignant traits to target cells is a potential pathway to explain cancer dissemination. Although these results were encouraging, they were never corroborated by data showing the molecular mechanisms responsible for the observed phenomenon.
Methods
In the present study, we exposed
BRCA1
-KO fibroblasts to extracellular vesicles (EVs) isolated from a colon cancer cell line (HT29) and from sera of patients with colorectal cancer. Three weeks after exposure, fibroblasts were injected subcutaneously into NOD-SCID mice. Whole genome sequencing, transcriptome analysis and RNA sequencing of cancer EVs and fibroblasts prior and after exposure to cancer EVs were performed.
Results
Phenotypical transformation of the fibroblasts into colon cancer cells was confirmed by histopathological study of the xenotransplants. We observed that EV-mediated transfer of cancer microRNAs was responsible for the transition from a mesenchymal to an epithelial phenotype (MET) in the treated fibroblasts as well as activation of cell cycle progression and cell survival pathways. DNA and RNA sequencing suggested that cancer DNA was transferred and possibly transcribed in target cells. Furthermore, injection of colon cancer EVs in the tail vein of NOD-SCID mice determined neoplastic transformation and metastases in the lungs of the mice confirming for the first time the hypothesis that transfer of malignant epithelial cancer traits to distant target cells is a concept applicable to in vivo models.
Conclusions
These discoveries shed new light into the molecular mechanisms behind the horizontal transfer of malignant traits and confirm the notion that metastatic disease might be reproduced through transfer of circulating genetic material.
Electronic supplementary material
The online version of this article (10.1186/s13046-019-1248-2) contains supplementary material, which is available to authorized users.
“…EVs regulate different biological functions via the transfer of their cargo into target cells [ 46 , 47 , 51 , 52 , 53 , 54 ]. We have previously demonstrated that blood-derived EVs from patients with ocular and cutaneous melanoma are uptaken by and reprogram single oncosuppressor-mutated (SOM), such as Fibro-BKO cells into malignant cells [ 46 , 47 , 48 ]. We wanted to investigate the behavior of Fibro-BKO cells and analyze their growth potential when exposed to either culture medium without EVs (No-EVs), NCM-EVs or UM-EVs.…”
Section: Resultsmentioning
confidence: 99%
“…We performed this study to investigate the effects of EVs derived from UM cell lines on the behaviour of target cells, and to compare the protein contents in EVs derived from UM cells and normal choroidal melanocytes (NCMs). We have previously demonstrated that blood-derived EVs from patients with ocular and cutaneous melanoma are uptaken by and reprogram single oncosuppressor-mutated (SOM) cells into malignant cells [ 46 , 47 , 48 ]. Here, we showed that as opposed to NCM-EVs, UM-EVs increased the proliferation of target SOM cells such as BRCA1-deficient fibroblasts (Fibro-BKO) and induced their malignant transformation.…”
Extracellular vesicles (EVs) carry molecules derived from donor cells and are able to alter the properties of recipient cells. They are important players during the genesis and progression of tumors. Uveal melanoma (UM) is the most common primary intraocular tumor in adults and is associated with a high rate of metastasis, primarily to the liver. However, the mechanisms underlying this process are poorly understood. In the present study, we analyzed the oncogenic potential of UM-derived EVs and their protein signature. We isolated and characterized EVs from five UM cell lines and from normal choroidal melanocytes (NCMs). BRCA1-deficient fibroblasts (Fibro-BKO) were exposed to the EVs and analyzed for their growth in vitro and their reprograming potential in vivo following inoculation into NOD-SCID mice. Mass spectrometry of proteins from UM-EVs and NCM-EVs was performed to determine a protein signature that could elucidate potential key players in UM progression. In-depth analyses showed the presence of exosomal markers, and proteins involved in cell-cell and focal adhesion, endocytosis, and PI3K-Akt signaling pathway. Notably, we observed high expression levels of HSP90, HSP70 and integrin V in UM-EVs. Our data bring new evidence on the involvement of UM-EVs in cancer progression and metastasis.
“…Exosomes produced by metastatic melanoma cells have been reported to contribute to premetastatic niche formation, preparing the environment for colonization by CTCs [77]. In a study on the use of oncosuppressor-mutated cell-based liquid biopsy tests for cancer screening, EVs from cancer patients of many tumor types, including choroidal melanoma, were capable of transforming oncosuppressor-mutated cells to form tumors in vivo, suggesting the horizontal transfer of malignant traits [78]. In-depth studies on UM-derived exosomes are limited, and characterization of EVs in this disease setting is lacking.…”
In the era of precision oncology, major strides are being made to use individual tumor information for clinical decision-making. Differing from traditional biopsy methods, the emerging practice of liquid biopsy provides a minimally invasive way of obtaining tumor cells and derived molecules. Liquid biopsy provides a means to detect and monitor disease progression, recurrence, and treatment response in a noninvasive way, and to potentially complement classical biopsy. Uveal melanoma (UM) is a unique malignancy, with diagnosis heavily reliant on imaging, few repeat biopsies, and a high rate of metastasis, which occurs hematogenously and often many years after diagnosis. In this disease setting, a noninvasive biomarker to detect, monitor, and study the disease in real time could lead to better disease understanding and patient care. While advances have been made in the detection of tumor-disseminated components, sensitivity and specificity remain important challenges. Ambiguity remains in how to interpret current findings and in how liquid biopsy can have a place in clinical practice. Related publications in UM are few compared to other cancers, but with further studies we may be able to uncover more about the biology of disseminated molecules and the mechanisms involved in the progression to metastasis.
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