Adipose Stem Cells and Cancer: Concise Review.

It is well established that the tumor microenvironment plays an important role in cancer development and progression. The tumor microenvironment is composed of neoplastic cells, endothelial cells, pericytes, adipocytes, fibroblasts and other connective tissue cells, extracellular matrix components, multiple stem and progenitor cells, and a diverse array of innate and adaptive immune cells [Nat Rev Cancer 2007;7:139-147]. Understanding the mechanisms behind cell-cell communication in the tumor microenvironment is critical to understanding the drivers of tumorigenesis and metastasis. In this review, we discuss the interactions between adipose stem cells, a critical component of the tumor microenvironment, and various forms of cancer. Stem Cells 2019;37:1261-1266.

Obesity-Altered Adipose Stem Cells Promote ER⁺ Breast Cancer Metastasis through Estrogen Independent Pathways.

Adipose stem cells (ASCs) play an essential role in tumor microenvironments. These cells are altered by obesity (obASCs) and previous studies have shown that obASCs secrete higher levels of leptin. Increased leptin, which upregulates estrogen receptor alpha (ERα) and aromatase, enhances estrogen bioavailability and signaling in estrogen receptor positive (ER⁺) breast cancer (BC) tumor growth and metastasis. In this study, we evaluate the effect of obASCs on ER⁺BC outside of the ERα signaling axis using breast cancer models with constitutively active ERα resulting from clinically relevant mutations (Y537S and D538G). We found that while obASCs promote tumor growth and proliferation, it occurs mostly through abrogated estrogen signaling when BC has constitutive ER activity. However, obASCs have a similar promotion of metastasis irrespective of ER status, demonstrating that obASC promotion of metastasis may not be completely estrogen dependent. We found that obASCs upregulate two genes in both ER wild type (WT) and ER mutant (MUT) BC: SERPINE1 and ABCB1. This study demonstrates that obASCs promote metastasis in ER WT and MUT xenografts and an ER MUT patient derived xenograft (PDX) model. However, obASCs promote tumor growth only in ER WT xenografts.

Ang-1 and Ang-2 expression in angiomyolipoma and PEComa family tumors.

OBJECTIVE: Perivascular epithelioid cell tumors (PEComa) are an uncommon family of soft tissue tumors. Previously, we described that the presence of pericyte antigens among PEComa family tumors differs extensively by histologic appearance. METHODS: Here, we extend our findings using the pericyte antigens Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2), using immunohistochemical detection in human tumor samples. RESULTS: While Ang-1 showed no expression across any PEComa family tumor, Ang-2 showed expression that like other pericyte markers was largely determined by cytologic appearance. CONCLUSION/IMPLICATIONS: Pericytic marker expression in PEComa may represent a true pericytic cell of origin, or alternatively aberrant pericyte marker adoption.

Ang-2 but not Ang-1 expression in perivascular soft tissue tumors.

Perivascular soft tissue tumors are relatively uncommon neoplasms of unclear line of differentiation, although most are presumed to originate from pericytes. Previously, we reported a shared immunophenotype across these related tumor types. Here, we extend these findings to examine the expression of the pericyte markers angiopoietin-1 and -2 (Ang-1 and -2) among perivascular soft tissue tumors. Results showed consistent Ang-2 but not Ang-1 expression across tumor types. In summary, the absence of Ang-1 expression distinguishes perivascular from vascular soft tissue tumors. Ang-2 expression is present across perivascular soft tissue tumors, with some variation between histologic subtypes.

Pericytic mimicry in well-differentiated liposarcoma/atypical lipomatous tumor.

Pericytes are modified smooth muscle cells that closely enwrap small blood vessels, regulating and supporting the microvasculature through direct endothelial contact. Pericytes demonstrate a distinct immunohistochemical profile, including expression of smooth muscle actin, CD146, platelet-derived growth factor receptor ß, and regulator of G-protein signaling 5. Previously, pericyte-related antigens have been observed to be present among a group of soft tissue tumors with a perivascular growth pattern, including glomus tumor, myopericytoma, and angioleiomyoma. Similarly, malignant tumor cells have been shown to have a pericyte-like immunoprofile when present in a perivascular location, seen in malignant melanoma, glioblastoma, and adenocarcinoma. Here, we examine well-differentiated liposarcoma specimens, which showed some element of perivascular areas with the appearance of smooth muscle (n = 7 tumors). Immunohistochemical staining was performed for pericyte antigens, including smooth muscle actin, CD146, platelet-derived growth factor receptor ß, and regulator of G-protein signaling 5. Results showed consistent pericytic marker expression among liposarcoma tumor cells within a perivascular distribution. MDM2 immunohistochemistry and fluorescence in situ hybridization for MDM2 revealed that these perivascular cells were of tumor origin (7/7 tumors), whereas double immunohistochemical detection for CD31/CD146 ruled out an endothelial cell contribution. These findings further support the concept of pericytic mimicry, already established in diverse malignancies, and its presence in well-differentiated liposarcoma. The extent to which pericytic mimicry has prognostic significance in liposarcoma is as yet unknown.