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Oncosuppressor-Mutated Cells as a Liquid Biopsy Test for Cancer-Screening.

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 mutations can uptake cancer factors and be used in biological based liquid biopsy tests. Our observations were confirmed in a large variety of solid and haematological malignancies. This test was able to detect dysplasia and carcinomas in situ lesions in different organs and circulating factors in cancer patients years after the removal of their lesions. To our knowledge, this ability is unique and not shared by other liquid biopsy platforms. Immunohistochemistry analysis of the xenotransplants revealed identical patterns of differentiation regardless of the cancer type, showing that differentiation through horizontal transfer might be dependent on the nature of the target cells rather than the type of cancer factors. These data strengthen the notion that OMC-based liquid biopsy tests might be promising platforms for cancer screening.

SUBMITTER: Abdouh M

PROVIDER: S-EPMC6382857 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Oncosuppressor-Mutated Cells as a Liquid Biopsy Test for Cancer-Screening.

Abdouh Mohamed M Gao Zu-Hua ZH Arena Vincenzo V Arena Manuel M Burnier Miguel N MN Arena Goffredo Orazio GO

Scientific reports 20190220 1

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 onco ...[more]

PMID: 30787346

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Project description:Horizontal transfer of malignant traits from the primary tumor to distant organs, through blood circulating factors, has recently become a thoroughly studied metastatic pathway to explain cancer dissemination. Recently, we reported that oncosuppressor gene-mutated human cells undergo malignant transformation when exposed to cancer patients' sera. We also observed that oncosuppressor mutated cells would show an increased uptake of cancer-derived exosomes and we suggested that oncosuppressor genes might protect the integrity of the cell genome by blocking integration of cancer-derived exosomes. In the present study, we tested the hypothesis that cancer patients' sera-derived exosomes might be responsible for the malignant transformation of target cells and that oncosuppressor mutation would promote their increased uptake. We also sought to unveil the mechanisms behind the hypothesized phenomena.We used human BRCA1 knockout (BRCA1-KO) fibroblasts as target cells. Cells were treated in vitro with cancer patients' sera or cancer patients' sera-derived exosomes. Treated cells were injected into NOD-SCID mice. Immunohistochemical analyses were performed to determine the differentiation state of the xenotransplants. Mass spectrometry analyses of proteins from cancer exosomes and the BRCA1-KO fibroblasts' membrane were performed to investigate possible de novo expression of molecules involved in vesicles uptake. Blocking of the identified molecules in vitro was performed and in vivo experiments were conducted to confirm the role of these molecules in the malignant transformation carried out by cancer-derived exosomes.Cells treated with exosomes isolated from cancer patients' sera underwent malignant transformation and formed tumors when transplanted into immunodeficient mice. Histological analyses showed that the tumors were carcinomas that differentiated into the same lineage of the primary tumors of blood donors. Oncosuppressor mutation promoted the de novo expression, on the plasma membrane of target cells, of receptors, responsible for the increased uptake of cancer-derived exosomes. The selective blocking of these receptors inhibited the horizontal transfer of malignant traits.These findings strengthen the hypothesis that oncogenic factors transferred via circulating cancer exosomes, induce malignant transformation of target cells even at distance. Oncosuppressor genes might protect the integrity of the cell genome by inhibiting the uptake of cancer-derived exosomes.

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Oncosuppressor-Mutated Cells as a Liquid Biopsy Test for Cancer-Screening.

Publications

Oncosuppressor-Mutated Cells as a Liquid Biopsy Test for Cancer-Screening.

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