Cross Talk Between Macrophages and Cancer Cells in the Bone Metastatic Environment

Batoon, Lena; McCauley, Laurie K.

doi:10.3389/fendo.2021.763846

Cited by 15 publications

(7 citation statements)

References 275 publications

(329 reference statements)

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“…Aberrant efferocytosis is associated with numerous inflammatory diseases, autoimmune disorders and cancers [ 46 – 48 ]. Among pertinent examples, failure to clear apoptotic bodies drives lesion progression and plaque stability in atherosclerosis [ 49 , 50 ] and in metastatic bone disease, macrophage efferocytosis of apoptotic cancer cells creates a microenvironment that promotes tumor progression [ 47 , 48 ]. The iCasp9 mice can facilitate further investigation into these pathologies focused at elucidating the phenotypes of defective efferocytosis that will inform the development of corrective strategies.…”

Section: Discussionmentioning

confidence: 99%

Caspase-9 driven murine model of selective cell apoptosis and efferocytosis

et al. 2023

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Apoptosis and efficient efferocytosis are integral to growth, development, and homeostasis. The heterogeneity of these mechanisms in different cells across distinct tissues renders it difficult to develop broadly applicable in vivo technologies. Here, we introduced a novel inducible caspase-9 (iCasp9) mouse model which allowed targeted cell apoptosis and further facilitated investigation of concomitant efferocytosis. We generated iCasp9+/+ mice with conditional expression of chemically inducible caspase-9 protein that is triggered in the presence of Cre recombinase. In vitro, bone marrow cells from iCasp9+/+ mice showed expression of the iCasp9 protein when transduced with Cre-expressing adenovirus. Treatment of these cells with the chemical dimerizer (AP20187/AP) resulted in iCasp9 processing and cleaved caspase-3 upregulation, indicating successful apoptosis induction. The in vivo functionality and versatility of this model was demonstrated by crossing iCasp9+/+ mice with CD19-Cre and Osteocalcin (OCN)-Cre mice to target CD19+ B cells or OCN+ bone-lining osteoblasts. Immunofluorescence and/or immunohistochemical staining in combination with histomorphometric analysis of EGFP, CD19/OCN, and cleaved caspase-3 expression demonstrated that a single dose of AP effectively induced apoptosis in CD19+ B cells or OCN+ osteoblasts. Examination of the known efferocytes in the target tissues showed that CD19+ cell apoptosis was associated with infiltration of dendritic cells into splenic B cell follicles. In the bone, where efferocytosis remains under-explored, the use of iCasp9 provided direct in vivo evidence that macrophages are important mediators of apoptotic osteoblast clearance. Collectively, this study presented the first mouse model of iCasp9 which achieved selective apoptosis, allowing examination of subsequent efferocytosis. Given its unique feature of being controlled by any Cre-expressing mouse lines, the potential applications of this model are extensive and will bring forth more insights into the diversity of mechanisms and cellular effects induced by apoptosis including the physiologically important efferocytic process that follows.

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Section: Discussionmentioning

confidence: 99%

Caspase-9 driven murine model of selective cell apoptosis and efferocytosis

et al. 2023

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“…This indicates that KIFC1 may play a part in regulating the polarization of TAM. Researchers have found that TAM can promote tumor cells’ growth and metastasis through a variety of pathways ( Batoon and McCauley, 2021 ; Kong et al, 2021 ). This could partly explain why KIFC1 can promote LIHC progress.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value and Immunological Role of KIFC1 in Hepatocellular Carcinoma

Han

et al. 2022

Front. Mol. Biosci.

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As one of the members of the kinesin family, the role and potential mechanism of kinesin family member C1 (KIFC1) in the development of liver hepatocellular carcinoma (LIHC), especially in the immune infiltration, have not been fully elucidated. In this study, multiple databases and immunohistochemistry were employed to analyze the role and molecular mechanism including the immune infiltration of KIFC1 in LIHC. Generally, KIFC1 mRNA expression was overexpressed in LIHC tissues than normal tissues, and its protein was also highly expressed in the LIHC. KIFC1 mRNA expression was correlated with tumor grade and TNM staging, which was negatively correlated with overall survival and disease-free survival. Moreover, univariable and multivariate Cox analysis revealed that upregulated KIFC1 mRNA is an independent prognostic factor for LIHC. The KIFC1 promoter methylation level was negatively associated with KIFC1 mRNA expression and advanced stages and grade in LIHC. The different methylation sites of KIFC1 had a different effect on the prognosis of LIHC. Specifically, the KIFC1 mRNA expression level showed intense correlation with tumor immunity, such as tumor-infiltrating immune cells and immune scores as well as multiple immune-related genes. Moreover, KIFC1 co-expressed with some immune checkpoints and related to the responses to immune checkpoint blockade (ICB) and chemotherapies. Significant GO analysis showed that genes correlated with KIFC1 served as catalytic activity, acting on DNA, tubulin binding, histone binding, ATPase activity, and protein serine/threonine kinase activity. KEGG pathway analysis showed that these genes related to KIFC1 are mainly enriched in signal pathways such as cell cycle, spliceosome, pyrimidine metabolism, and RNA transport. Conclusively, KIFC1 was upregulated and displayed a prognostic value in LIHC. Moreover, KIFC1 may be involved in the LIHC progression partially through immune evasion and serve as a predictor of ICB therapies and chemotherapies.

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“…In a PyMT mouse model, the expression of RANK in luminal BC led to the recruitment of TAMs and TANs, which inhibited T lymphocyte recruitment and/or activity [ 56 ]. CCL2 and CXCL12 are well-known key signaling pathways in BC bone metastases [ 57 , 58 ].…”

Section: The Cells Of Innate Immunity and Their Role According To The...mentioning

confidence: 99%

The Innate Immune Microenvironment in Metastatic Breast Cancer

Tommasi

Pellegrino

Diana³

et al. 2022

JCM

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The immune system plays a fundamental role in neoplastic disease. In the era of immunotherapy, the adaptive immune response has been in the spotlight whereas the role of innate immunity in cancer development and progression is less known. The tumor microenvironment influences the terminal differentiation of innate immune cells, which can explicate their pro-tumor or anti-tumor effect. Different cells are able to recognize and eliminate no self and tumor cells: macrophages, natural killer cells, monocytes, dendritic cells, and neutrophils are, together with the elements of the complement system, the principal players of innate immunity in cancer development and evolution. Metastatic breast cancer is a heterogeneous disease from the stromal, immune, and biological point of view and requires deepened exploration to understand different patient outcomes. In this review, we summarize the evidence about the role of innate immunity in breast cancer metastatic sites and the potential targets for optimizing the innate response as a novel treatment opportunity.

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Cross Talk Between Macrophages and Cancer Cells in the Bone Metastatic Environment

Cited by 15 publications

References 275 publications

Caspase-9 driven murine model of selective cell apoptosis and efferocytosis

Caspase-9 driven murine model of selective cell apoptosis and efferocytosis

Prognostic Value and Immunological Role of KIFC1 in Hepatocellular Carcinoma

The Innate Immune Microenvironment in Metastatic Breast Cancer

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