Intratumoral Adipocyte-High Breast Cancer Enrich for Metastatic and Inflammation-Related Pathways but Associated with Less Cancer Cell Proliferation.

Yoshihisa Tokumaru,Masanori Oshi,Masayuki Nagahashi,Manabu Futamura,Kazuhiro Yoshida,Nobuhisa Matsuhashi,Kazuaki Takabe,Li Yan,Jing Li Huang,Eriko Katsuta

doi:10.3390/ijms21165744

Abstract

Cancer-associated adipocytes are known to cause inflammation, leading to cancer progression and metastasis. The clinicopathological and transcriptomic data from 2256 patients with breast cancer were obtained based on three cohorts: The Cancer Genome Atlas (TCGA), GSE25066, and a study by Yau et al. For the current study, we defined the adipocyte, which is calculated by utilizing a computational algorithm, xCell, as “intratumoral adipocyte”. These intratumoral adipocytes appropriately reflected mature adipocytes in a bulk tumor. The amount of intratumoral adipocytes demonstrated no relationship with survival. Intratumoral adipocyte-high tumors significantly enriched for metastasis and inflammation-related gene sets and are associated with a favorable tumor immune microenvironment, especially in the ER+/HER2- subtype. On the other hand, intratumoral adipocyte-low tumors significantly enriched for cell cycle and cell proliferation-related gene sets. Correspondingly, intratumoral adipocyte-low tumors are associated with advanced pathological grades and inversely correlated with MKI67 expression. In conclusion, a high amount of intratumoral adipocytes in breast cancer was associated with inflammation, metastatic pathways, cancer stemness, and favorable tumor immune microenvironment. However, a low amount of adipocytes was associated with a highly proliferative tumor in ER-positive breast cancer. This cancer biology may explain the reason why patient survival did not differ by the amount of adipocytes.

Highlights

Breast cancer is one of the leading causes of cancer-related deaths in developed countries, including the United States [1,2]
We found intratumoral adipocyte-high tumors enriched for epithelial–mesenchymal transition (EMT), TGFβ signaling, angiogenesis, WNTβ catenin signaling, and Hedgehog signaling in the whole cohort and the ER+/HER2 subtype in The Cancer Genome Atlas (TCGA) (Figure 3B, Supplementary Figures S3B and S4B)
Given the data from the gene set enrichment analysis, we further explored the infiltration of immune cells within the tumor microenvironment using the whole TCGA breast cancer cohort

Summary

Introduction

Breast cancer is one of the leading causes of cancer-related deaths in developed countries, including the United States [1,2]. Numerous investigators, including our group, have reported that cancer cells and the tumor microenvironment plays a critical role in cancer progression and metastasis, as well as therapeutic responses [9,10]. Cancer-associated adipocytes interact with cancer cells and secrete the inflammatory cytokines, such as IL-6 and TNF-α, which contribute to pro-cancer inflammation that is known to aggravate cancer progression [23,24,25,26,27]. TNF-α promotes the invasion and metastasis of breast cancer by activating epithelial–mesenchymal transition (EMT) signaling [30,31,32]. Cancer-associated adipocytes secrete chemokines such as Chemokine (C–C motif) ligand 2 (CCL2), which activates NOTCH1 signaling pathway and induces the stemness of the cancer cells [22,33]. Leptin, which is produced by cancer-associated adipocytes, collaborates with IL-1, and promotes angiogenesis by upregulating expression of VEGF and VEGF receptors [22,34,35,36]

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Conclusion