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

Abstract

Chemotherapy is a double-edged sword. It is anticancer because of its cytotoxicity. Paradoxically, by increasing chemoresistance and cancer metastasis, it is also procancer. However, the underlying mechanisms for chemotherapy-induced procancer activities are not well understood. Here we describe the ability of paclitaxel (PTX), a frontline chemotherapeutic agent, to exacerbate metastasis in mouse models of breast cancer. We demonstrate that, despite the apparent benefit of reducing tumor size, PTX increased the circulating tumor cells in the blood and enhanced the metastatic burden at the lung. At the primary tumor, PTX increased the abundance of the tumor microenvironment of metastasis, a landmark microanatomical structure at the microvasculature where cancer cells enter the blood stream. At the metastatic lung, PTX improved the tissue microenvironment (the "soil") for cancer cells (the "seeds") to thrive; these changes include increased inflammatory monocytes and reduced cytotoxicity. Importantly, these changes in the primary tumor and the metastatic lung were all dependent on Atf3, a stress-inducible gene, in the noncancer host cells. Together, our data provide mechanistic insights into the procancer effect of chemotherapy, explaining its paradox in the context of the seed-and-soil theory. Analyses of public datasets suggest that our data may have relevance to human cancers. Thus, ATF3 in the host cells links a chemotherapeutic agenta stressor-to immune modulation and cancer metastasis. Dampening the effect of ATF3 may improve the efficacy of chemotherapy.chemotherapy | metastasis | stress response | immune modulation | ATF3 M odern chemotherapy can reduce tumors to an undetectable level; however, in many cases the tumors relapse, with recurrence in the original, regional, or distant sites (1-3). The mechanisms for relapse are multifaceted and complex, including intrinsic changes in cancer cells and changes in the noncancer cells in the host-the organism carrying the cancer (4-9). Although the traditional concept is that chemotherapeutic drugs provide selection pressure for drug-resistant cancer cells to thrive, recent studies showed that chemotherapeutic drugs actually induce procancer changes (reviewed in refs. 4-9 and in the references cited below). Thus, chemotherapy is a double-edged sword: It is anticancer because of its cytotoxicity on cancer cells but also can be procancer by inducing changes in cancer and/or host cells. For cancer cell-intrinsic changes, chemotherapeutic drugs have been shown to induce the migration/invasion of cancer cells (10) and to up-regulate the expression of some antiapoptotic genes (11). For noncancer cells, chemotherapy theoretically can affect all host cells, because it is administered systemically. Advances in this nascent field have benefited greatly from the extensive literature on cancerhost interaction in the recent decades (5-7, 12). Although endothelial cells have been shown to play a role in mediating the procancer effect of chemotherapy (13-15), various reports als...

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“…Chemotherapy-induced TMEM assembly and metastasis has been further corroborated by another research group using multiple models of breast carcinoma [6].…”

“…paclitaxel) and non-taxane (i.e doxorubicin and cyclophosphamide) chemotherapies [3]. Accordingly, Editorial stress-inducible genes, such as cyclic AMP-dependent transcription factor ATF3, appear to be non-cancer cell-associated master orchestrators of chemotherapyexacerbated breast cancer metastasis [6], further confirming a more generalized cytotoxic mechanism behind the chemotherapy-induced pro-metastatic phenotype. However, other researchers have indicated that certain chemotherapeutic drugs (e.g.…”

“…Therefore, the studies discussed in this context [2,3,6] provide valuable preclinical information, which may help elucidate this clinical paradox. In conclusion, metastasis promoters, such as TMEM and MENA isoforms including MENA INV , have the potential to promote the development of pro-metastatic tumor microenvironments in response neoadjuvant chemotherapy and should be investigated further in clinical trials, both as prognostic and predictive markers, as well as therapeutic targets.…”

Research Highlight: Neoadjuvant chemotherapy exacerbates breast cancer metastasis

“…Recent published work by Karagiannis and collaborators (Karagiannis, Pastoriza et al 2017), and Chang and colleagues (Chang, Jalgaonkar et al 2017) show that though neoadjuvant chemotherapy reduces tumor size, they also increase breast tumor metastasis. Karagiannis, et al using intra-vital imaging show that paclitaxel treated mice have greater vascular leakage and tumor cell dissemination, which occurs from specific site, which they define as the tumor microenvironment of metastasis (TMEM) site.…”

“…Although neoadjuvant therapy can reduce tumor size to nondistinguishable levels it does not improve overall patient survival (Rastogi, Anderson et al 2008, Gianni, Baselga et al 2009). This paradox is answered by new findings from Karagiannis and collaborators (Karagiannis, Pastoriza et al 2017), and Chang and colleagues (Chang, Jalgaonkar et al 2017) who show that though neoadjuvant chemotherapy reduces tumor size, they also increase breast tumor metastasis. …”