Epigenetic therapy can inhibit metastases by disrupting premetastatic niches ??

Many cancers are successfully treated with surgery, but there’s always the possibility of recurrence — at the surgical site or in a distant organ site. Consequently, surgery is often followed-up by adjuvant therapy (i.e. chemotherapy and/or radiotherapy to help decrease risk of the cancer recurring); these procedures help improve survival of the patient (preventing ‘relapse’) by killing cancer cells that remain at the surgical site or those that have already migrated elsewhere. However, adjuvant therapy is not always effective; it might not prevent certain processes that aid cancer resurgence (e.g. recruitment of white blood cells — called myeloid cells — to distant organs, where they can help malignant cells to ‘settle down’ and ‘thrive’).

Authors [see attached article & editorial] show how the chemical structure of DNA in the myeloid-cell nucleus is an “Achilles heel” that might “able to be controlled” — by targeting these tumor-promoting cells and limiting cancer spread. When tumor cells spread from its primary site to distant organs (called ‘metastasis’), this requires complex interactions between malignant cells and surrounding healthy tissues. Evidence is growing that primary cancers can produce signals that modify normal cells to generate a “favorable medium” in distant organs — termed a pre-metastatic niche — that “allows” subsequent “seeding”’ and establishment of cancer cells at a secondary site. These metastatic tumors are the ones that are often lethal to the patient.

Authors [see article] reveal that — after surgical removal of primary lung and other types of cancer, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both formation and growth of lung metastases through the selective effects on myeloid-derived suppressor cells (MDSCs). In mouse models of lung metastases, MDSCs are key factors in formation of the premetastatic microenvironment after resection of primary tumors. Adjuvant epigenetic therapy — which uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat — disrupts the premetastatic niche by inhibiting the trafficking of MDSCs [via down-regulating the CCR2 (C-C motif chemokine receptor-2) and CXCR2 (C-X-C motif chemokine receptor-2) genes], and by promoting MDSC differentiation into a more mature macrophage-like phenotype.

Decreased accumulation of MDSCs in the premetastatic lung therefore produces longer periods of disease-free survival and increased overall patient survival — compared with chemotherapy. These data demonstrate that, even after removal of the primary tumor, these nasty MDSCs contribute to the development of premetastatic niches and settlement of residual tumor cells. This combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic

microenvironment and inhibits metastases [detailed in this article] may permit a “favorable adjuvant approach to cancer therapy” in the near future. 😊

DwN

Nature 12 Mar 2020; 579: 284-290 + Editorial pp 196-197

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