Editors' ChoiceCancer

Aging is just a state of marrow

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Science Translational Medicine  07 Aug 2019:
Vol. 11, Issue 504, eaay7698
DOI: 10.1126/scitranslmed.aay7698

Abstract

Aging induces proliferation of bone marrow progenitor cells and disseminated tumor cells, leading to therapeutic resistance and bone metastasis.

Bone is the leading metastatic site for hormone-dependent cancers. Our current understanding of bone metastasis is based on preclinical animal models utilizing young mice that are not skeletally mature or representative of the patient population, which is likely to be middle-aged or older. As aging has profound effects on the bone microenvironment, this mismatch between the patient population and the animals studied has prevented the development of effective bone metastasis–targeting therapies.

In a recent publication, Singh et al. found that aging induced the proliferation of pericytes, hematopoietic stem cells, mesenchymal stem cells, and disseminated tumor cells, releasing them from quiescence. Intracardiac injection of human breast cancer cell lines resulted in larger bone metastases in aged mice compared with young mice. RNA-sequencing showed that quiescence-promoting genes were down-regulated in the aged bone marrow, leading to an altered secretome that induced breast cancer cell proliferation. To better mimic the clinical regimen, mice were treated with a single dose of three Gray gamma radiation or platinum analog chemotherapy before tumor injection, which induced quiescence-promoting growth factor secretion and pericyte numbers. Treating mice with prazosin or clonidine reduced blood flow to the bones after chemotherapy or radiation and prevented breast cancer cell colonization of the bone marrow. Thus, initial systemic treatment may increase the number of pericytes maintaining disseminated tumor cells in a dormant state. As patients age, the numbers of pericytes begin to decrease, which may lead to the reactivation of cancer cells and the development of macrometastases.

Further studies are needed to examine the role of sex hormones and skeletal integrity with aging and dormant tumor cell reactivation. The young mice used were not skeletally or sexually mature and were more representative of humans younger than 20 years of age, whereas the aged mice were likely undergoing menopause with early osteoporosis representing humans between 45 to 60 years of age. Other age groups are needed to understand the spectrum of age- and hormone-related alterations in the bone microenvironment and their effects on tumor cell dormancy. Additionally, syngeneic tumor cell injection or humanized mouse studies are needed to examine the role of the immune system in cancer cell reactivation during aging. This research is the first step in developing more clinically relevant models for targeting cancer bone metastasis. These initial findings indicate that adjuvant treatment with blood flow–reducing agents may prevent tumor cell colonization during the treatment of primary hormone-dependent cancers.

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