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Reciprocal Network Between Cancer Stem-Like Cells and Macrophages Published OnlineFirst April 24, 2018; DOI: 10.1158/1078-0432.CCR-18-0461 Translational Cancer Mechanisms and Therapy Clinical Cancer Research Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer Hai Huang1, Chao Wang1, Fei Liu1, Hui-Zhen Li1, Guang Peng1, Xu Gao1, Ke-Qin Dong1, Hong-Ru Wang1, De-Pei Kong1, Min Qu1, Li-He Dai1, Kai-Jian Wang1, Zhe Zhou1, Jun Yang1, Ze-Yu Yang1, Yan-Qiong Cheng1, Qin-Qin Tian1, Dan Liu1, Chuan-Liang Xu1, Dan-Feng Xu2, Xin-Gang Cui3,4, and Ying-Hao Sun1 Abstract Purpose: Cancer stem-like cells (CSC) contribute to the pro- Results: Autophagy-related gene 7 (ATG7) facilitated the gression and androgen deprivation therapy (ADT) resistance transcription of OCT4 via b-catenin, which binds to the OCT4 of prostate cancer. As CSCs depend on their specificniche, promoter, promoting CSC characteristics in prostate cancer, including tumor-associated macrophages (TAM), elucidating including self-renewal, tumor initiation, and drug resistance. the network between CSCs and TAMs may help to effectively In addition, CSCs remodeled their specific niche by educating inhibit the progression and ADT resistance of prostate cancer. monocytes/macrophages toward TAMs, and the CSC-educat- Experimental Design: The underlying intracellular ed TAMs reciprocally promoted the stem-like properties of mechanism that sustains the stem-like characteristics of CSCs, progression and ADT resistance of prostate cancer via CSCs in prostate cancer was assessed via RNA sequencing, IL6/STAT3. Furthermore, the combined targeting of CSCs and co-immunoprecipitation, chromatin immunoprecipitation, their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 and other assays. A coculture system and cytokine antibody receptor effectively ameliorated ADT resistance in an ortho- arrays were used to examine the interaction network between topic prostate cancer model. CSCs and TAMs. In addition, an orthotopic prostate cancer Conclusions: Targeting CSCs and their niche may prove to model was established to evaluate the in vivo effects of the be a more powerful strategy than targeting CSCs alone, pro- combined targeting of CSCs and their interaction with TAMs viding a rational approach to ameliorating ADT resistance in on ADT resistance. prostate cancer. Clin Cancer Res; 24(18); 4612–26. Ó2018 AACR. Introduction hierarchical organization of cells, offer an explanation for het- erogeneity among cancer cells (2). In different types of tumors, Intratumor heterogeneity promotes tumor evolution and con- CSCs are functionally defined by their strong stem-like properties tributes to disease progression, therapeutic failure, and patient including self-renewal, chemoresistance, tumor initiation upon survival (1). Cancer stem-like cells (CSC), a small subset of the serial passages, and metastatic potential (3, 4). Thus, elucidating the molecular mechanisms responsible for CSCs would help to develop new and promising therapies for advanced tumors in 1 Department of Urology, Changhai Hospital, Second Military Medical University, clinical practice. Shanghai, China. 2Department of Urinary Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 3Department of Urinary Prostate cancer, with its strong heterogeneity, remains one of – Surgery, The Third Affiliated Hospital of Second Military Medical University the most common causes of male cancer related deaths world- (Eastern Hepatobiliary Surgery Hospital), Shanghai, China. 4Department of wide (5). Androgen deprivation therapy (ADT), when applied to Urinary Surgery, Gongli Hospital, Second Military Medical University, Shanghai, advanced and recurrent prostate cancers, achieves short-term China. effectiveness, but ultimately induces drug resistance, leading to Note: Supplementary data for this article are available at Clinical Cancer increased cancer-related deaths (6, 7). Increasing evidence has Research Online (http://clincancerres.aacrjournals.org/). indicated that ADT induces reprogramming of prostate cancer and H. Huang, C. Wang, and F. Liu contributed equally to this article. enriches a subpopulation of cells with CSC properties, which are Corresponding Authors: Ying-Hao Sun, Department of Urology, Changhai resistant to ADT and drive prostate cancer progression (8, 9). Hospital, Second Military Medical University, 168 Changhai Road, Shanghai Therefore, eliminating CSCs may be crucial for achieving a good 200438, China. Phone/Fax: 8602-1350-30006; E-mail: [email protected]; response of prostate cancer to ADT. and Xin-Gang Cui, Department of Urinary Surgery, The Third Affiliated Hospital Intracellular programs including pluripotency transcription of Second Military Medical University (Eastern Hepatobiliary Surgery Hospital), factors (OCT4, Nanog, Sox2, etc.; refs. 10, 11) and aberrant 700 North Moyu Road, Shanghai 201805, China. Phone/Fax: 8602-1818-87661; signaling pathways (Wnt/b-catenin, STAT3, NFkB, etc.; refs. 12– E-mail: [email protected] 14) play a crucial role in maintaining the stem-like properties of doi: 10.1158/1078-0432.CCR-18-0461 CSCs. Autophagy, a highly conserved catabolic process that func- Ó2018 American Association for Cancer Research. tions as a cell survival mechanism under external stimuli such as 4612 Clin Cancer Res; 24(18) September 15, 2018 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst April 24, 2018; DOI: 10.1158/1078-0432.CCR-18-0461 CSC-Mø Facilitates the Progression and ADT Resistance of PCa Changzheng Hospital (Shanghai, China) between 2012 and Translational Relevance 2013. Patients enrolled in these two cohorts were pathologically Androgen deprivation therapy (ADT), when applied to diagnosed as prostate cancer without distant metastasis and advanced and metastatic prostate cancers, is initially effective underwent radical prostatectomy. Patients who received addi- but inevitably induces drug resistance. Many studies have tional treatment such as ADT, radiotherapy, or chemotherapy indicated that ADT induces heterogeneity, including cancer were not included. Follow-up time was 42 (6–62) months. Tumor stem-like cells (CSC), which are resistant to ADT and drive the stage and Gleason Scores (GS) were assessed in terms of the progression of prostate cancer. In fact, the specific microenvi- American Joint Committee on Cancer (AJCC) 2002 and the World ronment should receive equal consideration in eradicating Health Organization (WHO) classification guidelines. The time to CSCs and reversing the drug resistance of prostate cancer. In biochemical recurrence (BCR; cutoff: PSA ¼ 0.2 ng/mL) and this study, we demonstrated that the combined targeting of disease progression identified by MRI, CT, or ECT were selected CSCs and their interaction with tumor-associated macro- as the clinical endpoint of BCR-free survival and disease-free phages (TAM) by inhibiting autophagy-related gene 7 survival, respectively. Except for the two cohorts as above, this (ATG7)/OCT4 and IL6 receptor (IL6R) effectively ameliorated study also included patients who were pathologically diagnosed ADT resistance in an orthotopic prostate cancer model. Our castration-resistant prostate cancer (CRPC; n ¼ 10) in which study indicates that targeting CSCs jointly with their niche may 5 patients' samples were taken before and after ADT and NEPC prove to be a more powerful strategy than targeting CSCs (n ¼ 6) in Changhai Hospital (Shanghai, China). The samples alone, which provides a rational approach to ameliorating were obtained after writing informed consent from patients ADT resistance in prostate cancer. according to an established protocol approved by the Ethics Committee of Second Military Medical University. IHC The IHC was done as reported previously (24). Primary anti- chemotherapy or radiotherapy, has recently been shown to sup- bodies were used as follows: mouse anti-OV6 (MAB2020, R&D port tumor cell survival, differentiation, and the self-renewal of Systems), rat anti-F4/80 (ab6640, Dako), mouse anti-CD68 CSCs (15, 16). However, the related mechanisms need further (M0876, Dako), and rabbit anti-ATG7 (ab52472), mouse anti- study. b-catenin (ab22656), mouse anti-OCT4 (ab184665), and rabbit In addition to their internal characteristics, CSCs reside in anti-STAT3 (ab68153) from Abcam, respectively. The protein niches that support their self-renewal (17). Recent studies indicate expression was score by staining intensity and percentage of that CSCs remodel their specific niche by recruiting monocytes positively stained cells as reported previously (28). Hematoxylin and educating them to become tumor-associated macrophages and eosin (H&E)-stained sections of the prostate cancer (TAM; ref. 18). Furthermore, the CSC–TAM cross-talk facilitates specimens were reevaluated by two experienced pathologists tumor growth, metastasis, and chemoresistance (19, 20). Thus, (Jun-hui Ge and Yong-wei Yu, Second Military Medical Univer- jointly targeting CSCs and their niche components may prove to sity, Shanghai, China) to identify representative areas in double prevent tumor drug resistance and progression more effectively blind procedure. The percentage of positive cells (% of PPs) and than targeting the CSCs alone. Although our studies and others the staining intensity (SI value) were determined and multiplied have shown that ADT-induced transdifferentiation attracts the (IRS value), and the score range
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