Bone marrow adipocytes induce cancer‐associated fibroblasts and immune evasion, enhancing invasion and drug resistance

Abstract

Bone metastasis occurs frequently in cancer patients. Conventional therapies have limited therapeutic outcomes, and thus, exploring the mechanisms of cancer progression in bone metastasis is important to develop new effective therapies. In the bone microenvironment, adipocytes are the major stromal cells that interact with cancer cells during bone metastasis. However, the comprehensive functions of bone marrow adipocytes in cancer progression are not yet fully understood. To address this, we investigated the role of bone marrow adipocytes on cancer cells, by focusing on an invasive front that reflects the direct effects of stromal cells on cancer. In comprehensive histopathological and genetic analysis using bone metastasis specimens, we examined invasive fronts in bone metastasis and compared invasive fronts with adipocyte-rich bone marrow (adipo-BM) to those with hematopoietic cell-rich bone marrow (hemato-BM) as a normal counterpart of adipocytes. We found morphological complexity of the invasive front with adipo-BM was significantly higher than that with hemato-BM. Based on immunohistochemistry, the invasive front with adipo-BM comparatively had a significantly increased cancer-associated fibroblast (CAF) markerpositive area and lower density of CD8 + lymphocytes compared to that with hemato-BM. RNA sequencing analysis of primary and bone metastasis cancer revealed that bone metastasized cancer cells acquired drug resistance-related gene expression phenotypes. Clearly, these findings indicate that bone marrow adipocytes provide a favorable tumor microenvironment for cancer invasion and therapeutic resistance of bone metastasized cancers through CAF induction and immune evasion, providing a potential target for the treatment of bone metastasis.

Histological findings of thyroid cancer after lenvatinib therapy

“…Coagulative necrosis and ischaemic changes in cancer cells were semiquantitatively assessed 8 . Furthermore, microvessel density (MVD) was evaluated according to previously described methods 9,10 . Photographs of CD31‐stained sections were subjected to binarisation using Fiji 11 .…”

“…8 Furthermore, microvessel density (MVD) was evaluated according to previously described methods. 9,10 Photographs of CD31-stained sections were subjected to binarisation using Fiji. 11 Subsequently, statistical analyses were conducted.…”

Therapeutic Potential of Tumor Metabolic Reprogramming in Triple-Negative Breast Cancer

“…Remodeling of the extracellular matrix of the surrounding adjacent tumor area may also be associated with adipocytes, as the release of collagen VI and matrix metalloproteinase 11 (MMP11) promotes cancer invasion [ 26 ] ( Figure 2 ). It has been described that adipocytes also promote invasion and drug resistance by inducing CAFs in bone marrow metastases [ 27 ].…”

“…Remodeling of the extracellular matrix of the surrounding adjacent tumor area may also be associated with adipocytes, as the release of collagen VI and matrix metalloproteinase 11 (MMP11) promotes cancer invasion [26] (Figure 2). It has been described that adipocytes also promote invasion and drug resistance by inducing CAFs in bone marrow metastases [27]. In CAF cells with increased glycolysis, uptaken glucose is converted to lactate, which is driven by increased efflux to tumor cells through higher MCT4 (monocarboxylate transporter 4) levels.…”

Metabolomics combined with mathematical analysis reveals metabolic pathways specific to metastatic cancers

“…In addition to glucose and amino acid metabolism, fatty acid metabolism is also important in intracellular metabolism of metastatic cancers ( 14 - 16 ), and it has been pointed out that stromal cells, such as adipocytes surrounding cancer cells, may contribute to cancer cell metabolism owing to substantial alterations in the microenvironment at metastatic sites ( 17 ). Further development of research on the intracellular metabolism of cancer is anticipated in the near future.…”