Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells

Jinushi, Masahisa; Chiba, Shigeki; Yoshiyama, Hironori; Masutomi, Kenkichi; Kinoshita, Ichiro; Dosaka‐Akita, Hirotoshi; Yagita, Hideo; Takaoka, Akinori; Tahara, Hideaki

doi:10.1073/pnas.1106645108

Cited by 429 publications

(358 citation statements)

References 38 publications

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“…Ablation of SK4, however, had a minor effect on mean survival rates but did not significantly prolong tumour‐free survival nor overall survival in the MMTV‐PyMT tg/+ model (Fig. 4), possibly due to an impaired immune and/or stromal cell response, which results in a tumour progression‐promoting microenvironment (Jinushi et al ., 2011; Loeffler et al ., 2006; Wiseman and Werb, 2002) that counteracts the loss of the oncogenic SK4 functions in the tumour cells. The difference in tumour formation time between SK4‐deficient and SK4‐proficient MMTV‐PyMT tumour cells transplanted orthotopically into WT mice strongly supports this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

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Oncogenic signalling via Ca2+‐activated K+ channels of intermediate conductance (SK4, also known as KCa3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumorigenesis is unclear. Herein, we generated SK4‐negative tumours by crossing SK4‐deficient (SK4 KO) mice to the polyoma middle T‐antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promoter MMTV. Survival parameters and tumour progression were studied in cancer‐prone SK4 KO in comparison with wild‐type (WT) mice and in a syngeneic orthotopic mouse model following transplantation of SK4‐negative or WT tumour cells. SK4 activity was modulated by genetic or pharmacological means using the SK4 inhibitor TRAM‐34 in order to establish the role of breast tumour SK4 for cell growth, electrophysiological signalling, and [Ca2+]i oscillations. Ablation of SK4 and TRAM‐34 treatment reduced the SK4‐generated current fraction, growth factor‐dependent Ca2+ entry, cell cycle progression and the proliferation rate of MMTV‐PyMT tumour cells. In vivo, PyMT oncogene‐driven tumorigenesis was only marginally affected by the global lack of SK4, whereas tumour progression was significantly delayed after orthotopic implantation of MMTV‐PyMT SK4 KO breast tumour cells. However, overall survival and progression‐free survival time in the MMTV‐cNeu mouse model were significantly extended in the absence of SK4. Collectively, our data from murine breast cancer models indicate that SK4 activity is crucial for cell cycle control. Thus, the modulation of this channel should be further investigated towards a potential improvement of existing antitumour strategies in human breast cancer.

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Section: Discussionmentioning

confidence: 99%

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

et al. 2017

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“…We assessed tumor associated macrophages (TAMs) because of their role in tumor angiogenesis and sensitivity to anticancer treatments [31]. Steidl et al [32] suggested that the expression of CD68, a pan-macrophages endosomal glycoprotein, is the best biomarker for macrophages.…”

Section: Discussionmentioning

confidence: 99%

A phase II study of neoadjuvant bevacizumab plus capecitabine and concomitant radiotherapy in patients with locally advanced rectal cancer

et al. 2012

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Purpose To assess safety and activity of neoadjuvant bevacizumab, capecitabine and standard radiotherapy in locally advanced rectal cancer as well as potential predictive biomarkers. Patients and methods The multicentric phase II study enrolled 43 patients who received bevacizumab infusion (5 mg/kg) every 2 weeks for 4 cycles; oral capecitabine at 825 mg/m 2 twice a day for 5.5 weeks with external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks). We determined certain biomarkers before and after therapy for correlation with response.Results Post-operative histologic examination revealed no residual cancer cells in 6 of the 43 patients (14%; 95% confidence limits 3.60-24.31%). In another 22 patients (51.2%) a varying percentage of cancer cells in residual areas of fibrosis/ necrosis was found, corresponding to Mandard TRG 2 or 3 classification. Tumor resection with negative circumferential margin was achieved in 38/40 (95%) operated patients. Sphincter-sparing surgery was obtained in 31 (72.1%) patients. Primary tumor and lymph nodes downstaging was observed in 15 (34.9%) and 16 (37.2%) cases, respectively. Neoadjuvant therapy was safe and well tolerated. The most frequent side effects were G1-2 diarrhea, proctitis, rectal bleeding and hypertension. No biomarker tested was significantly predictive of both pathological complete response and disease-free survival. Pre-treatment CD-34 vessel density, post-treatment Ki-67 labeling index and VEGFR-2 cancer cells expression significantly correlated with residual tumor area. Conclusions The schedule of neoadjuvant therapy tested was safe and active. Pre-treatment vessel density by the panendothelial marker anti CD-34 antibody, post-treatment Ki-67 labeling index and VEGFR-2 expression were significantly associated to residual tumor area. The biomarkers correlations warrant further evaluation in prospective clinical trials.

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“…In cancer, populations of tumor-associated macrophages (TAMs) mediate immunosuppression and possess M2-like qualities, such as poor antigen presentation, promotion of angiogenesis, and tissue remodeling and repair, although there is heterogeneity in pathways and phenotypes in different tumors (5). TAMs also secrete the factors milk fat globule-EGF factor 8 and IL-6 that lead to tumorigenicity and drug resistance of cancer stem/initiating cells (6). The extent of TAM accumulation within tumors generally correlates with poor disease prognosis (7,8).…”

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confidence: 99%

Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival

Cieslewicz

Tang

Yu³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Tumor-associated macrophages (TAMs) are cells of our innate immune system that have been associated with poor prognosis in many types of cancers. When polarized toward the anti-inflammatory state, TAMs promote immune evasion and angiogenesis, thereby driving tumor growth. Using a peptide library selection strategy, we identified a sequence, called M2pep, that preferentially binds to anti-inflammatory murine macrophages. We then used M2pep to carry a proapoptotic peptide to TAMs by i.v. delivery and demonstrated that selective reduction of TAMs resulted in improved survival in tumor-bearing mice. These results suggest that a molecular-targeting approach for TAM depletion is a promising adjunct strategy to add to the arsenal of anticancer therapies.

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Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells

Cited by 429 publications

References 38 publications

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

A phase II study of neoadjuvant bevacizumab plus capecitabine and concomitant radiotherapy in patients with locally advanced rectal cancer

Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival

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Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells

Cited by 429 publications

References 38 publications

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

A phase II study of neoadjuvant bevacizumab plus capecitabine and concomitant radiotherapy in patients with locally advanced rectal cancer

Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival

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SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer

SK4 channels modulate Ca²⁺ signalling and cell cycle progression in murine breast cancer