Chan et al. report that treatment of tumor-bearing mice with low-dose metronomic chemotherapy prevents stromal secretion of ELR+ chemokines and induction of tumor-initiating cells usually observed with administration of drugs at maximum tolerated dose.

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Whilst traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. Treatment resistance and metastasis have been attributed to expansion of cancer stem-like cells (CSCs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy-treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximal tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts that induces the expression and secretion of ELR-motif-positive (ELR+) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into CSCs and promote their invasive behaviors, leading to paradoxical tumor aggression following the therapy. By contrast, the same total accumulated dose administered as a low-dose-metronomic chemotherapy regimen largely prevented the therapy-induced stromal ELR+-chemokine paracrine signaling for CSCs, thereby substantially enhancing treatment response and extending survival of mice carrying desmoplastic cancers (Chan et al, J. Exp. Med. 2016). These studies illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy. Note: This abstract was not presented at the meeting. Citation Format: Kelvin K. Tsai, Tze-Sian Chan, Chung-Chi Hsu, Vincent C. Pai, Shenq-Shyang Huang, Valerie M. Weaver. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4763. doi:10.1158/1538-7445.AM2017-4763

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Metastasis is the major cause of cancer mortality in androgen-independent prostate cancer (PCA) and understanding it is crucial to improving the outcome of patients. Recent evidence suggests that activation of Wnt signaling in cancer stem cells (CSCs) contributes to cancer progression in malignant tumors. Here we report that a novel Wnt activator ASPM (Abnormal spindle-like microcephaly associated) maintains the prostate CSC subpopulation through augmenting the Wnt-β-catenin signaling in PCA. Functional studies showed that downregulation of ASPM expression attenuated the proliferation and invasive of PCA cells and reduced the number of prostate CSCs and inhibited cancer stemness and tumorigenesis. Mechanistically, ASPM interacts with dishevelled-3 (Dvl-3) and inhibits its proteasome-dependent degradation, thereby increasing the protein stability of Dvl-3 and enabling the β-catenin transcriptional activity in PCA cells. The clinical significance of the above findings was credentialed by the profound up-regulation of ASPM in metastatic PCA and the strong correlation of cytoplasmic ASPM expression with poor metastasis-free survival of patients with resected PCA. Collectively, our data points to ASPM as a novel oncoprotein and an essential regulator of cancer stemness in PCA, which has important clinical and therapeutic significance (supported by Ministry of Science and Technology grants MOST 104-2314-B-400-022 and MOST 105-2314-B-400-018 and National Health Research Institutes NHRIs grant CA-106-PP-09 to K.K.T). Citation Format: Kelvin K. Tsai, Vincent C. Pai, Chung-Chi Hsu, Tze-Sian Chan. ASPM promotes prostate cancer tumorigenesis by bolstering cancer stemness through Wnt-Dvl-3-b-catenin signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 538.