Emergence of Cancer-Associated Fibroblasts as an Indispensable Cellular Player in Bone Metastasis Process

Mukaida, Naofumi; Zhang, Di; Sasaki, Soichiro

doi:10.3390/cancers12102896

Cited by 27 publications

(26 citation statements)

References 126 publications

(147 reference statements)

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“…In this study, using a 3D microfluidic platform, we modelled the reciprocal interaction between CAFs and breast carcinoma cells. Using our invasion and migration model, we demonstrated that CAFs promote spheroid formation and the migration capacity of carcinoma cells [15], possibly through the secretion of cancer-promoting cytokines that play a haptotactic or chemotactic role for carcinoma cells [52]. Following treatment with PFD, we found that PFD significantly reduced the migration of an invasive type of breast cancer cells and CAFs, and significantly decreased the expression of EMT marker vimentin, stemness marker CD44, and YAP1 in CAF-tumor spheroids at the protein level [41].…”

Section: Discussionmentioning

confidence: 92%

Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)

Cox

Sarafraz-Yazdi

et al. 2021

Cancers

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The aim of this study was to assess the effects of pirfenidone (PFD) on promoting epithelial–mesenchymal-transition (EMT) and stemness features in breast carcinoma cells through targeting cancer-associated-fibroblasts (CAFs). Using The Cancer Genome Atlas (TCGA) database, we analyzed the association between stromal index, EMT, and stemness-related genes across 1084 breast cancer patients, identifying positive correlation between YAP1, EMT, and stemness genes in samples with a high-stromal index. We monitored carcinoma cell invasion and spheroid formation co-cultured with CAFs in a 3D microfluidic device, followed by exposing carcinoma cells, spheroids, and CAFs with PFD. We depicted a positive association between the high-stromal index and the expression of EMT and stemness genes. High YAP1 expression in samples correlated with more advanced EMT status and stromal index. Additionally, we found that CAFs promoted spheroid formation and induced the expression of YAP1, VIM, and CD44 in spheroids. Treatment with PFD reduced carcinoma cell migration and decreased the expression of these genes at the protein level. The cytokine profiling showed significant depletion of various EMT- and stemness-regulated cytokines, particularly IL8, CCL17, and TNF-beta. These data highlight the potential application of PFD on inhibiting EMT and stemness in carcinoma cells through the targeting of critical cytokines.

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Section: Discussionmentioning

confidence: 92%

Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)

Cox

Sarafraz-Yazdi

et al. 2021

Cancers

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“…One of the important reasons is tumor cell-stromal cell interactions (40). This preferential [ 68 Ga]Ga-DOTA-FAPI-04 accumulation is likely associated with the presence of CAFs in tumor stroma of bone metastases (41).…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Relative Diagnostic Performance of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT for the Detection of Bone Metastasis in Patients With Different Cancers

Wang

Liao

et al. 2021

Front. Oncol.

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PurposeThe present retrospective analysis sought to compare the relative diagnostic efficacy of [68Ga]Ga-DOTA-FAPI-04 to that of [18F]FDG PET/CT as a means of detecting bone metastases in patients with a range of cancer types.MaterialsIn total, 30 patients with bone metastases associated with different underlying malignancies were retrospectively enrolled. All patients had undergone [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT, and the McNemar test was used to compare the relative diagnostic performance of these two imaging modalities. The maximum standard uptake value (SUVmax) was used to quantify radiotracer uptake by metastatic lesions, with the relative uptake associated with these two imaging strategies being compared via the Mann-Whitney U test. The cohort was further respectively divided into two (osteolytic and osteoblastic bone metastases) and three clinical subgroups (lung cancer, thyroid cancer, and liver cancer).Results[68Ga]Ga-DOTA-FAPI-04 PET/CT was found to be significantly more sensitive as a means of diagnosing bone metastases relative to [18F]FDG PET/CT ([109/109] 100% vs [89/109] 81.7%; P< 0.01), consistent with the significantly increased uptake of [68Ga]Ga-DOTA-FAPI-04 by these metastatic lesions relative to that of [18F]FDG (n=109, median SUVmax, 9.1 vs. 4.5; P< 0.01). [68Ga]Ga-DOTA-FAPI-04 accumulation was significantly higher than that of [18F]FDG in both osteolytic (n=66, median SUVmax, 10.6 vs 6.1; P < 0.01), and osteoblastic metastases (n=43, median SUVmax, 7.7 vs 3.7; P < 0.01). [68Ga]Ga-DOTA-FAPI-04 uptakes were significantly higher than that of [18F]FDG in bone metastases from lung cancer (n = 62, median SUVmax, 10.7 vs 5.2; P < 0.01), thyroid cancer (n = 18, median SUVmax, 5.65 vs 2.1; P < 0.01) and liver cancer (n = 12, median SUVmax, 5.65 vs 3.05; P < 0.01). However, [68Ga]Ga-DOTA-FAPI-04 detected 10 false-positive lesions, while only 5 false-positive were visualized by [18F]FDG PET/CT.Conclusion[68Ga]Ga-DOTA-FAPI-04 PET/CT exhibits excellent diagnostic performance as a means of detecting bone metastases, and is superior to [18F]FDG PET/CT in this diagnostic context. Furthermore, [68Ga]Ga-DOTA-FAPI-04 tracer uptake levels are higher than those of [18F]FDG for most bone metastases. However, owing to the potential for false-positive bone lesions, it is critical that physicians interpret all CT findings with caution to ensure diagnostic accuracy.

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“…Similarly, macrophages were shown to play an important role in tumor recurrence and metastatic outgrowth in murine models (206,(315)(316)(317)(318)(319). During the metastatic cascade, CAFs and M2 macrophages can collaborate in altering the functions of other stromal cells as well as the tumor cells (250,320). Nielsen et al reported that early recruitment of granulin secreting inflammatory monocytes to the liver is very important for pancreatic ductal adenocarcinoma liver metastasis.…”

Section: The Effects On Tumor Progressionmentioning

confidence: 99%

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

Günaydın

2021

Front. Oncol.

121

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Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) are among the most important and abundant players of the tumor microenvironment. CAFs as well as TAMs are known to play pivotal supportive roles in tumor growth and progression. The number of CAF or TAM cells is mostly correlated with poor prognosis. Both CAFs and TAMs are in a reciprocal communication with the tumor cells in the tumor milieu. In addition to such interactions, CAFs and TAMs are also involved in a dynamic and reciprocal interrelationship with each other. Both CAFs and TAMs are capable of altering each other’s functions. Here, the current understanding of the distinct mechanisms about the complex interplay between CAFs and TAMs are summarized. In addition, the consequences of such a mutual relationship especially for tumor progression and tumor immune evasion are highlighted, focusing on the synergistic pleiotropic effects. CAFs and TAMs are crucial components of the tumor microenvironment; thus, they may prove to be potential therapeutic targets. A better understanding of the tri-directional interactions of CAFs, TAMs and cancer cells in terms of tumor progression will pave the way for the identification of novel theranostic cues in order to better target the crucial mechanisms of carcinogenesis.

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Emergence of Cancer-Associated Fibroblasts as an Indispensable Cellular Player in Bone Metastasis Process

Cited by 27 publications

References 126 publications

Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)

Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)

Comparison of the Relative Diagnostic Performance of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT for the Detection of Bone Metastasis in Patients With Different Cancers

CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion

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