PNAS Plus: Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis

Atf3, a stress-inducible gene, in the noncancer host cells.nHighlight:recent studies showed that chemotherapeutic drugs actually induce procancer changesnHighlight:chemotherapeutic drugs have been shown to induce the migration/invasion of cancer cellsnHighlight:p-regulate the expression of some antiapoptotic genes nHighlight:Atf3 in the noncancer host cells (referred to hereafter as “host-Atf3”) is necessary for efficient metastasisnHighlight:Atf3 is induced by various chemotherapeutic drugs, including PTX (), cisplatin (), and doxorubicinnHighlight:Tie2-expressing monocytes/macrophages (TEMs; markers CD11+, F4/80+, TIE2+), a subset of macrophages that is proangiogenicnHighlight: TEMs isolated from the WT-PTX tumors stimulated cancer cell invasionnHighlight:PTX affects the activity of TEMnHighlight: Cancer cells enter the blood vessels (intravasate) at sites with a microanatomical landmark called “tumor microenvironment of metastasis” (TMEM), a structure composed of a perivascular macrophage and a cancer cell in close proximitynHighlight:PTX increases TMEMs in a host-Atf3–dependent manner.nHighlight: PTX further increased CTCsnHighlight:CTCs were much higher in WT than in Atf3-KO mice, indicating that host-Atf3 facilitates cancer cell escapenHighlight:higher CTC numbers in WT than in Atf3-KO micenHighlight:PTX can enhance the ability of cancer cells to escape from tumors and to colonize the second site.nHighlight:PTX treatment, however, enhanced both seeding and immunosuppression in a host-Atf3–dependent mannernHighlight:despite the apparent therapeutic benefit of reducing tumor size, PTX enhances the dissemination of cancer cells (the seeds) from primary tumors and facilitates the preparation of the lung microenvironment (the soil) to be more hospitable to cancer cells, thereby explaining the paradoxical procancer effect of chemotherapy in the context of the seed-and-soil theory (). (ii) The report delineates a pathway from chemotherapy to stress responsnHighlight:despite the apparent therapeutic benefit of reducing tumor size, PTX enhances the dissemination of cancer cells (the seeds) from primary tumors and facilitates the preparation of the lung microenvironment (the soil) to be more hospitable to cancer cells, thereby explaining the paradoxical procancer effect of chemotherapy in the context of the seed-and-soil theorynHighlight:chemotherapy to stress response, to immune modulation and metastasis, with Atf3nHighlight:cellular stress response has evolved to promote tissue repair but has been co-opted to help cancer cell survival and progressionnHighlight:chemotherapy, as a stressor, can counteract its own efficacy by inducing a stress responsenHighlight: a stress response in both noncancer cells (our study) and cancer cells (the PPIA study) can counteract chemotherapynHighlight:PTX decreases pericyte coverage but increases TMEM, CTCs, seeding, iMs, and immune-suppression, all in a host-Atf3–dependent mannernHighlight:PTX decreases pericyte coverage but increases TMEM, CTCs, seeding, iMs, and immune-suppression, all in a host-Atf3–dependent manner. None of these effects has been reported before. Although cisplatin, a different chnHighlight:cisplatin, a different chemotherapeutic drug, has been shown to increase seedingnHighlight: PTX increases TMEMnHighlight: iMs have been shown to enhance metastasinHighlight: iMs have been shown to enhance metastasisn]]>

About Dr. Nathan Goodyear
About Dr. Nathan Goodyear

Dr. Nathan Goodyear, a medical doctor with years of experience in the field of integrative cancer care, has announced the launch of an online training program. This program, available on his new website, will provide individuals with access to video trainings led by Dr. Goodyear himself, covering a range of topics related to integrative cancer care. These trainings will include information on the latest research and techniques in the field, as well as guidance on how to incorporate these approaches into a patient’s overall cancer treatment plan. With this online program, Dr. Goodyear hopes to make his expertise and knowledge more widely accessible, and help more people understand the benefits of integrative cancer care.

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