Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis.

Sharon Lim,Kayoko Hosaka,Yihai Cao,Masaki Nakamura

doi:10.18632/oncotarget.9436

Abstract

Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth.

Highlights

Microvasculature distributed in various tissues exhibit marked differences in their density, structure, architecture, and functions
To investigate the variation of pre-existing vascular beds in different tissues in modulating tumor growth, we chose subcutaneous tissue, white adipose tissue (WAT) and brown adipose tissue (BAT) for our study. Immunohistochemical staining of these tissues show that inguinal WAT and interscapular BAT contained substantially higher density of microvessel than the subcutaneous tissue (P < 0.001) (Figure 1A)
Under the experimental temperature condition (22-23 °C), a www.impactjournals.com/oncotarget substantial number of interscapular BAT (iBAT) adipocytes expressed UCP1, which is a key mitochondrial protein responsible for nonshivering thermogenesis (Figure 1A and 1B). It appeared that iBAT contained fewer inflammatory macrophages relative to subcutaneous and inguinal WAT (iWAT) tissues (P < 0.01) (Figure 1A and 1B)

Summary

Introduction

Microvasculature distributed in various tissues exhibit marked differences in their density, structure, architecture, and functions. Adipose tissues, especially brown adipose tissue (BAT) is probably the most vascularized tissue in the body [1,2,3,4]. Adipose tissue is probably the largest endocrine organ in the body and adipocytes produce various adipokines, hormones, growth factors, and cytokines to regulate its local microenvironment and the distal macroenvironment [4, 7,8,9,10,11,12,13]. To cope with alterations of adipocytes, the adipose vasculature exhibits marked plasticity during adipose tissue expansion and shrinkage [14, 15]

Methods

Results

Conclusion