Tumor initiation and progression rely on the dynamic interactions between malignant tumor cells and multiple normal cell types within its microenvironment such as fibroblasts, various immune cells, endothelial cells, and adipocytes. Of these cell types, adipocytes are probably the least well studied, although they represent a significant part of the tissue surrounding a tumor [
28]. Emerging evidence suggests that adipocytes should not be considered simply as an energy-storage depot. Instead, adipose tissue can play a central role in both endocrine and metabolic processes by producing a battery of factors including growth factors and adipokines [
29]. Thus, understanding how obesity and adipose tissue-related factors are connected to tumor development is paramount. In 2010, Dirat’s group coined the term “cancer-associated adipocytes (CAA)” to demonstrate the bidirectional crosstalk between breast cancer cells and tumor-surrounding adipocytes and that CAA are a key player in tumor progression [
30]. Subsequently, several studies also showed the existence of the putative CAA in the vicinity of cancer cells [
31,
32]. Here, we chose adipocytes as a cellular model which are differentiated by culturing human MSCs under adipogenic conditions and are fully characterized by morphology, staining, and marker gene expression. We demonstrated that HCC cell line HepG2-derived exosomes could be actively incorporated by adipocytes and convert adipocytes into tumor-promoting cells (exo-adipocytes). In the mouse xenograft model, we found that exo-adipocytes promoted tumor growth and enhanced angiogenesis. Fujisaki et al. reported that in the presence of breast cancer cell lines MCF7 and MDA-MB-231, adipocytes reverted to an immature and proliferative phenotype of CAA that could promote cancer cell migration [
33].
Lee et al. found that when indirectly co-cultured with breast cancer cells, adipocytes would be transited into CAA, resulting in proliferation-enhancing effect in ER-positive breast cancer cells such as MCF7 and ZR-75-1 but not in ER-negative cells [
34]. Thus, we postulate that the exo-adipocytes in our study are a kind of CAA as they exhibit tumor-promoting capacity and higher expression of pro-inflammatory factors such as IL-6, IL-8, and MCP-1 whose higher expression in CAA has been reported [
33,
34]. IL-6 plays diverse regulatory roles in cancer pathogenesis including remodeling the tumor microenvironment, activation of EMT process, and promoting drug resistance [
35,
36]. IL-8 is known to be a stimulatory factor for tumor angiogenesis [
37], and MCP-1 promotes the recruitment of macrophages into tumors [
38]. These cytokines may be at least partially responsible for the tumor-promoting and angiogenesis-enhancing effects of exo-adipocytes.
The regulatory mechanisms of the CAA transition are not clearly understood. In this study, we explored the role of HCC-derived exosomes on the cellular and molecular changes of exo-adipocytes, which further confirmed that tumor cells could use exosomes as a novel way of cell-cell communication. Our study is consistent with previous findings that tumor exosomes from various cancer types can “educate” neighboring cells such as MSCs [
39], endothelial cells [
40], monocytes [
41], and dendritic cells [
42]. For example, exosomes from ovarian and breast cancer cells can convert adipose-derived MSCs (AMSC) into myofibroblast-like cells [
43,
44] while prostate cancer cell-derived exosomes trigger bone marrow MSCs (BMSC) to differentiate into pro-angiogenic and pro-invasive myofibroblasts [
45]. Our results support the postulation that the elements of adipose tissue can also be modified by cancer cells and participate in a highly complex vicious cycle to form a tumor-favorable microenvironment.
How exosomes cause significant cellular and molecular changes in target cells remains an area of intensive research. Using microarray, Fang et al. found that HCC exosomes could deliver miR-1247-3p into fibroblasts and converted them into cancer-associated fibroblast to foster lung metastasis [
46]. Using proteomic analysis,
He et al. revealed that exosomes derived from metastatic HCC cell lines carried a large number of protumorigenic proteins, such as MET protooncogene, S100 family members, and the caveolins [
19]. Here, we also detected common exosomal markers, structure or surface proteins, exosomal formation or secretion-related proteins, and oncogenic proteins in HepG2 exosomes. Upon taking up HCC exosomes, 725 upregulated and 648 downregulated genes were identified, and several cell signaling pathways were activated. In our previous study [
24], we found that lung tumor exosomes could activate NFκB signaling pathway through HSP70/TLR2. Here, we also detected the activation of the NFκB signaling pathway. However, several questions remain for future investigation, including which receptors on the surface of adipocytes participated in HCC exosome internalization and how the internalized exosome cargos activated the downstream signaling pathways.