Pathologic evaluation of tumor-associated macrophage density and vessel inflammation in invasive breast carcinomas

Morita, Yoshihiro; Zhang, Roy; Leslie, Macall; Adhikari, Smita; Hasan, Nafis; Chervoneva, Inna; Rui, Hallgeir; Tanaka, Takemi

doi:10.3892/ol.2017.6466

Cited by 32 publications

(21 citation statements)

References 49 publications

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“…For example, TAMs can process cleavable ADCs through FcRgmediated interactions to produce free drug, resulting in antitumor activity (42). Indeed, we saw an abundance of TAMs within the necrotic core of these tumors, which is a common feature of solid tumors (40,50), and one which may enable release of free drug because we show that antibody-bound dead cells are internalized by macrophages in vitro. Others have indicated that the release of reducing agents by dead tumor cells can cleave disulfide linkers (45), which may be one mechanism by which DAB4-ADC with disulfide linkers are cleaved independently of internalization.…”

Section: Discussionmentioning

confidence: 72%

“…For the LL2 cells, SG3199 was the most potent with an IC 50 of 1 pmol/L, followed by Duocarmycin DM (142 pmol/L) and MMAE (687 pmol/L) compared with 1.5 mmol/L for cisplatin. Although A549 cells were more resistant, SG3199 was also the most potent inhibitor of A549 cell survival (IC 50 16 pmol/L), followed by duocarmycin DM, MMAE, and cisplatin (IC 50 399 pmol/L, 844 pmol/L, and 6.8 mmol/L respectively; Fig. 4A).…”

Section: Effect Of Free Drugs On Cell Survivalmentioning

confidence: 98%

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APOMAB Antibody–Drug Conjugates Targeting Dead Tumor Cells are Effective In Vivo

Staudacher

Liapis

et al. 2019

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC) have revolutionized the field of cancer therapy. ADCs combine the high specificity of tumor-targeting monoclonal antibodies with potent cytotoxic drugs, which cannot be used alone because of their high toxicity. Till date, all ADCs have either targeted cell membrane proteins on tumors or the tumor vasculature and microenvironment. Here, we investigate ADCs of APOMAB (DAB4, or its chimeric derivative, chDAB4), which is a mAb targeting the La/SSB protein, which is only accessible for binding in dying or dead cancer cells. We show that DAB4-labeled dead cells are phagocytosed by macrophages, and that the apoptotic/ necrotic areas within lung tumor xenografts are bound by DAB4 and are infiltrated with macrophages. We show that only DAB4-ADCs with a cleavable linker and diffusible drug are effective in two lung cancer models, particularly when given after chemotherapy. These results are consistent with other recent studies showing that direct internalization of ADCs by target cells is not essential for ADC activity because the linker can be cleaved extracellularly or through other mechanisms. Rather than targeting a tumor cell type specific antigen, DAB4-ADCs have the advantage of targeting a common trait in most solid tumors: an excess of post-apoptotic, necrotic cells either adjacent to hypoxic tumor regions or distributed more generally after cytotoxic therapy. Consequently, any antitumor effects are solely the result of bystander killing, either through internalization of the dead, ADC-bound tumor cells by macrophages, or extracellular cleavage of the ADC in the tumor microenvironment. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A.H. Staudacher, V. Liapis Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.

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Section: Discussionmentioning

confidence: 72%

Section: Effect Of Free Drugs On Cell Survivalmentioning

confidence: 98%

APOMAB Antibody–Drug Conjugates Targeting Dead Tumor Cells are Effective In Vivo

Staudacher

Liapis

et al. 2019

Molecular Cancer Therapeutics

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“…24,25 Several studies have reported that CCL2 and the inflammatory environment promote the malignant behavior of different tumors. [26][27][28] Xu et al found that CCL2 recruits monocytes to the TME and polarizes macrophages into the M2 type. 25 Secretion of CCL2 is also an important manifestation of TAM polarization in macrophages.…”

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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“…For example, similar to the finding in this study that metastatic ccRCC exhibited higher expression of CD163, it was reported that high CD163 expression in the adipose stroma of breast cancer independently predicted shorter cancer-specific survival [210]. However, unlike the result in another study based in the US, which found a prognostic potential for CD68 in discriminating invasive (high expression) and benign (low expression) breast tumours [213], CD68 expression levels in the perinephric adipose tissue in this present study did not show any discriminative potential for metastatic and non-metastatic ccRCC. The discrepancy may be due to different quantification methods: subjective semi-quantitative evaluation was applied in the previous study, whereas objective digital quantification was applied in this present study based on three thresholding.…”

Section: Discussionsupporting

confidence: 83%

The role of the adipose tissue microenvironment in kidney cancer

Shen¹

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Obesity increases the risk of tumourigenesis, but paradoxically may predict better prognosis after cancer has been diagnosed. There is a general lack of understanding of interactions between cancer cells and adipose tissue. Obesity is characterised by activated endoplasmic reticulum (ER) stress and increased infiltration of macrophages in the adipose tissue. Little is known about the connection between the ER stress and infiltration of macrophages in the adipose tissue. Additionally, the impact of each characteristic on the biology of cancer cells is unclear. This PhD project attempted to define the adipose tissue microenvironment in the setting of cancer, in particular, kidney cancer. The thesis adds knowledge that helps to define the heterogeneous adipose tissue microenvironment and its functions in cancer development.The thesis is presented as a literature review (Chapter 1) followed by four original research sections (Chapters 2-5) that have, in some cases, been published (Chapter 2) or submitted (Chapters 3 and 4).The literature review (Chapter 1) will initially introduce the epidemiology, pathophysiology and prognostic factors for kidney cancer, followed by a summary of the advances in biomarker discovery in renal cell carcinoma (RCC). The literature review then introduces the structure, function and signaling pathways of the ER, followed by a discussion of the involvement of ER stress in cancer.The crosstalk between obesity, cancer and ER stress is also discussed. Finally, the role of macrophages in the tumour microenvironment is summarised.Chapter 2 is an immunohistochemistry-based retrospective cross-sectional study. Software-assisted quantification of staining intensity and proportion of positive pixels was applied to measure expression of glucose-regulated-protein-78/GRP78 (an ER stress marker) in archived specimens of renal tumour tissues (n=114), adjacent non-neoplastic renal tissues (n=68), and perinephric adipose tissues (n=60) in participants diagnosed with clear cell RCC (ccRCC), the commonest subtype of the RCC. Results demonstrated that GRP78 was not an optimal risk stratification marker for ccRCC.However, upregulated GRP78 in perinephric adipose tissue may be linked with a lower chance of metastasis.Chapter 3 introduces a liquid-overlay based method to generate reproducible and functional mature adipocyte spheroids using human perinephric adipose tissue-derived mesenchymal stem cells and the murine 3T3-L1 cell line. The established adipocyte spheroids were responsive to the ER stress activator, tunicamycin. and could secrete adiponectin, monocyte chemoattractant protein-1 (MCP-1) and interleukin/IL-8. Hence, the three-dimensional culture platform was able to serve as an adipose tissue microenvironment that could be applied in in vitro experiments.ii In Chapter 4, macrophage behaviour in the adipose tissue microenvironment was investigated using the 3D culture platform introduced in Chapter 3. Co-culture experiments were performed to measure the polarisation, migration and invasion of murine an...

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Pathologic evaluation of tumor-associated macrophage density and vessel inflammation in invasive breast carcinomas

Cited by 32 publications

References 49 publications

APOMAB Antibody–Drug Conjugates Targeting Dead Tumor Cells are Effective In Vivo

APOMAB Antibody–Drug Conjugates Targeting Dead Tumor Cells are Effective In Vivo

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

The role of the adipose tissue microenvironment in kidney cancer

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