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    Home > Biochemistry News > Biotechnology News > Nature Cancer: Reprogrammed macrophages stimulate vascular cells to secrete proteins and promote cancer metastasis

    Nature Cancer: Reprogrammed macrophages stimulate vascular cells to secrete proteins and promote cancer metastasis

    • Last Update: 2022-05-13
    • Source: Internet
    • Author: User
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    Research by scientists at the German Cancer Research Center (DKFZ) and HI-STEM has found that metastatic breast cancer cells use macrophages, a type of immune cell, to promote the resolution of lung cancer metastasis
    .
    The team's experiments in mice transplanted with human breast cancer cells showed that the reprogrammed macrophages stimulated vascular cells to secrete a mix of metastasis-promoting proteins that are part of the metastatic niche

    .
    The findings allow researchers to identify new targets and potential therapeutic avenues for inhibiting breast cancer metastasis

    .

    Research team leader Dr Thordur Oskarsson from DKFZ and HI-STEM said: "The complexity of the interactions between cancer cells, macrophages and endothelial cells is striking
    .
    With a better understanding of other factors, we were able to identify the starting point for a wide variety of new strategies to combat breast cancer metastasis

    .
    We have developed initial therapeutic concepts for this, which we now need to validate in further studies

    .
    "

    Oskarsson and colleagues published the paper in the journal Nature Cancer
    .
    In their paper, the team concluded, "The results show a critical role for the vascular niche in the metastatic process and underscore the role of the extracellular matrix in its regulation

    .
    These interactions in metastatic nodules may serve as To
    develop effective targets for the future treatment of metastatic disease

    .
    "

    Cancer cells spread throughout the body, with individual cells detached from the primary tumor and metastasized to distant areas of the body through the blood or lymphatic system
    .
    Before they can grow into metastases at a second site, these cells must communicate with their new environment through various molecular interactions

    .
    "To adapt to this new, hostile environment, cancer cells disrupt the microenvironment to support their growth," said Oscarson, now at the H.
    Lee Moffitt Cancer Center and Institute

    .
    The researchers call this a "metastatic niche" created by tumor cells

    .

    Blood vessels play a very specific role in metastasis
    .
    Isolated tumor cells prefer to stay near them

    .
    In particular, as many studies have shown, the interaction of cancer cells with endothelial cells (ECs) lining blood vessels is critical for metastasis

    .
    However, the details of this molecular exchange remain largely unknown

    .
    The authors further noted, "Recent findings suggest that blood vessels can have a substantial impact on metastatic progression beyond nutrient delivery

    .
    Studies have shown that disseminated cancer cells are associated with the vasculature at the site of metastasis, and suggest that enhanced adhesion and interaction with Crosstalk of ECs modulates phenotype and function of metastatic cancer cells

    .
    "

    Oskarsson and colleagues investigated the interaction between cancer cells and ECs during the metastatic colonization of breast cancer cells in the lungs of experimental mice
    .
    The researchers first observed that four genes in lung endothelial cells showed a particularly strong increase in activity three weeks after metastasis occurred

    .
    These genes encode proteins Inhbb, Lama1, Scgb3a1, and Opg, which are secreted into the microenvironment and, alone or in combination, promote the development of lung metastases

    .
    Inhbb (inhibin beta B) and Scgb3a1 (secretin 3A1) confer stem cell properties to cancer cells, Opg (osteoprotegerin) prevents programmed cell death-apoptosis, and Lama1 (laminin subunit alpha 1) supports adhesion mediators induced cell survival

    .

    Importantly, high expression of these four newly discovered niche factors was also found to be associated with shorter recurrence-free survival and overall survival in breast cancer patients
    .
    "…We performed a Kaplan-Meier analysis using the expression of four vascular niche components in estrogen receptor-negative breast cancer samples and investigated potential associations with survival," the team reports

    .
    "In these samples, vascular niche factor expression was significantly associated with poorer recurrence-free and overall survival, suggesting a potential role in breast cancer

    .
    "

    But how do cancer cells acquire the lung endothelium to produce a cocktail of proteins that promote metastasis? To the scientists' surprise, the cancer cells themselves did not do the job directly, but instead used macrophages, a type of cells of the innate immune system type
    .

    "These macrophages normally reside near pulmonary blood vessels and are activated by tenascin, an extracellular matrix protein produced by breast cancer cells," explained Tsunaki Hongu, PhD, a HI-STEM postdoc and first author of the study
    .
    In many cancers, tenascin is involved in disease progression

    .
    After macrophages are activated by tenascin, they produce various factors to induce ECs to produce oncoprotein cocktails

    .
    The authors further comment: "Stimulation of toll-like receptor 4 (TLR4)-activated perivascular macrophages by tenascin C (TNC) was shown to induce EC-mediated ec-mediated induction of nitric oxide (NO) and tumor necrosis factor (TNF) through secretion of nitric oxide (NO) and tumor necrosis factor (TNF).
    The production of niche components is critical for activating the niche

    .
    Notably, this mechanism is independent of vascular endothelial growth factor (VEGF), a key regulator of EC behavior and angiogenesis

    .
    "

    The researchers eliminated macrophages or their activity using specific molecular preparations to demonstrate that these cells are critical for producing a protein cocktail that promotes metastasis
    .
    "Targeting macrophage-mediated vascular niche activation and VEGF-regulated angiogenesis enhances the ability to inhibit lung metastasis in mice," they wrote

    .
    "In conclusion, our results describe distinct endothelial activation properties in which Macrophage-mediated inflammation induces the production of vascular niche proteins, and VEGF signaling promotes EC proliferation

    .

    The team concludes that their results provide new insights into the role of the extracellular matrix in cancer metastasis and point to potential therapeutic avenues
    .
    "The findings reveal a key interaction in the vascular microenvironment and underscore the importance of extracellular matrix proteins as regulators of the microenvironment in metastasis,

    " they wrote.
    "These results provide new insights into exploring TLR4i in combination with anti-VEGF therapy.
    Inhibition of vascular function in metastases provides a rationale

    .
    "

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