Breast cancer stem cells as last soldiers eluding therapeutic burn: A hard nut to crack

Nilendu, Pritish; Kumar, Ajay; Kumar, Azad; Pal, Jayanta K.; Sharma, Nilesh Kumar

doi:10.1002/ijc.30898

Cited by 31 publications

(35 citation statements)

References 168 publications

(340 reference statements)

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“…2d). PCSCs are considered as the origin and driving force of prostate cancer progression and metastasis 26,27 . CSCs are enriched in non-adherent spherical clusters of cells, which are termed mammospheres 28 .…”

Section: Tams-secreted Ccl5 Promotes the Invasion And The Pcscs Subpomentioning

confidence: 99%

CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling

et al. 2020

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Prostate cancer stem cells (PCSCs) play a critical role in prostate cancer progression and metastasis, which remains an obstacle for successful prostate cancer treatment. Tumor-associated macrophages (TAMs) are the most abundant immune cell population within the tumor microenvironment (TME). Systematic investigation of the interaction and network signaling between PCSCs and TAMs may help in searching for the critical target to suppress PCSCs and metastasis. Herein, we demonstrated that TAMs-secreted CCL5 could significantly promote the migration, invasion, epithelial-mesenchymal transition (EMT) of prostate cancer cells as well as the self-renewal of PCSCs in vitro. QPCR screening validated STAT3 as the most significant response gene in prostate cancer cells following CCL5 treatment. RNA-sequencing and mechanistic explorations further revealed that CCL5 could promote PCSCs self-renewal and prostate cancer metastasis via activating the β-catenin/STAT3 signaling. Notably, CCL5 knockdown in TAMs not only significantly suppressed prostate cancer xenografts growth and bone metastasis but also inhibited the self-renewal and tumorigenicity of PCSCs in vivo. Finally, clinical investigations and bioinformatic analysis suggested that high CCL5 expression was significantly correlated with high Gleason grade, poor prognosis, metastasis as well as increased PCSCs activity in prostate cancer patients. Taken together, TAMs/CCL5 could promote PCSCs self-renewal and prostate cancer metastasis via activating β-catenin/STAT3 signaling. This study provides a novel rationale for developing TAMs/CCL5 as a potential molecular target for PCSCs elimination and metastatic prostate cancer prevention.

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Section: Tams-secreted Ccl5 Promotes the Invasion And The Pcscs Subpomentioning

confidence: 99%

CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling

et al. 2020

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“…7,8 The relevance of this tumor heterogeneity is linked to various hallmarks of cancer including drug resistance. [9][10][11][12][13][14] Macrophages are diverse cells that show distinct phenotypes depending on their anatomical location and activating stimuli. 15,16 In breast cancer, macrophages can comprise up to 50% of the TME.…”

Section: Introductionmentioning

confidence: 99%

Tumor‐associated macrophages secrete CC‐chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer

et al. 2019

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Abbreviations: CCL2, CC-chemokine ligand 2; CM, conditioned medium; ER, estrogen receptor; MCP-1, monocyte chemoattractant protein 1; MR, tumor-associated macrophage from a tamoxifen-resistant tumor microenvironment; MS, tumor-associated macrophage from a tamoxifen-sensitive tumor microenvironment; PFS, progression-free survival; TAM, tumor-associated macrophage; TME, tumor microenvironment. AbstractBreast cancer is the most prevalent malignancy among women. Although endocrine therapy is effective, the development of endocrine resistance is a major clinical challenge. The tumor microenvironment (TME) promotes tumor malignancy, and tumor-associated macrophages (TAM) within the TME play a crucial role in endocrine resistance. Herein, we aimed to elucidate the relationship between TAM and the endocrine-resistant phenotype of breast cancer. Macrophages were cultured with conditioned medium (CM) from tamoxifen-sensitive (MCF7-S) or -resistant (MCF7-R) MCF7 breast cancer cells. M2 polarization was detected by CD163 immunofluorescence. To determine the effect on endocrine resistance, MCF7 cells were cultured in the supernatant of different TAM, and then treated with tamoxifen. CC-chemokine ligand 2 (CCL2) immunohistochemistry was carried out on pathological sections from 100 patients with invasive estrogen receptor-positive breast cancer. We found that macrophages cultured in the CM of MCF7-S and MCF7-R cells were induced into TAM, with a more obvious M2 polarization in the latter. Tamoxifen resistance was increased by culture in TAM medium. TAM secreted CCL2, which increased endocrine resistance in breast cancer cells through activation of the PI3K/Akt/mTOR signaling pathway. High expression of CCL2 was correlated with infiltration of CD163+macrophages (r = 0.548, P < .001), and patients with high CCL2 expression presented shorter progression-free survival than those with low CCL2 expression (P < .05). We conclude that CCL2 secreted by TAM activates PI3K/Akt/mTOR signaling and promotes an endocrine resistance feedback loop in the TME, suggesting that CCL2 and TAM may be novel therapeutic targets for patients with endocrineresistant breast cancer.

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“…Work by our group supports the connection between EMT and BCSCs by demonstrating that overexpression of the homeobox transcription factor, Six1, in a mammary gland-specific Six1-overexpressing transgenic mouse model increased the CSC pool while simultaneously producing tumors that exhibited a partial EMT phenotype (McCoy et al, 2009). Furthermore, several recent studies demonstrated that tumor-initiating ability of mesenchymal tumor-initiating cells was abolished when they were converted into epithelial counter parts (Avgustinova and Benitah, 2016;Chakraborty et al, 2016;Nilendu et al, 2018). These findings suggest contexts in which dynamic interplay between EMP and stemness can lead to distinct cancer cell populations with unique characteristics and activities.…”

Section: Cancer Stem Cell and Emt Plasticity In Breast Tumorigenesismentioning

confidence: 86%

Cellular Plasticity in Breast Cancer Progression and Therapy

Kong

Hughes

Ford

2020

Front. Mol. Biosci.

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With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women, with the majority of mortality being attributable to metastatic disease. Thus, even with improved early screening and more targeted treatments which may enable better detection and control of early disease progression, metastatic disease remains a significant problem. While targeted therapies exist for breast cancer patients with particular subtypes of the disease (Her2+ and ER/PR+), even in these subtypes the therapies are often not efficacious once the patient's tumor metastasizes. Increases in stemness or epithelial-to-mesenchymal transition (EMT) in primary breast cancer cells lead to enhanced plasticity, enabling tumor progression, therapeutic resistance, and distant metastatic spread. Numerous signaling pathways, including MAPK, PI3K, STAT3, Wnt, Hedgehog, and Notch, amongst others, play a critical role in maintaining cell plasticity in breast cancer. Understanding the cellular and molecular mechanisms that regulate breast cancer cell plasticity is essential for understanding the biology of breast cancer progression and for developing novel and more effective therapeutic strategies for targeting metastatic disease. In this review we summarize relevant literature on mechanisms associated with breast cancer plasticity, tumor progression, and drug resistance.

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Breast cancer stem cells as last soldiers eluding therapeutic burn: A hard nut to crack

Cited by 31 publications

References 168 publications

CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling

CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling

Tumor‐associated macrophages secrete CC‐chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer

Cellular Plasticity in Breast Cancer Progression and Therapy

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