Abstract
Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored.Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 + ), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.
Highlights
Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death
As the obesity inflammatory environment is strongly sustained by the paracrine activity of mature adipocytes and adipose-derived vascular stromal cells[37], including adipose stem cells, we investigated whether this cell subset is present in the tumor area and could influence cancer cell phenotype
We found that a high percentage of cells within tumor-neighboring and -infiltrating adipose tissue of patients with obesity are CD34 + /CD45, while lacking the expression of CD31, indicating their adipose stromal cells (ASCs) identity in both primary and metastatic Colorectal cancer (CRC)
Summary
Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. White AT is characterized by a marked cell variety, which includes adipocytes, immune cells, vascular, and progenitor cells[6] In obesity state, both the subcutaneous and visceral white adipose tissues expand by hypertrophy of pre-existing adipocytes. Recent evidence showed that visceral fat, in high-fat diet-induced obese mouse models, determines a hyperplastic response, which is driven by adipose precursor cells, identified as Lin– /Sca1+/CD29 + /CD34 + 7. This phenomenon could be due to the different embryological origin of subcutaneous and visceral adipose tissue, and/or by the presence of specific resident factors, as highlighted by lineage tracing experiment performed in adult Wt1-GFP knock-in mice[8]. Our data indicate microenvironmental cytokines as essential prognostic molecules that predict the tumor behavior of obesityassociated cancer patients
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