Heterogeneity and immunophenotypic plasticity of malignant cells in human liposarcomas

Abstract

Liposarcomas are tumors arising in white adipose tissue (WAT) with avidity for local recurrence. Aggressive dedifferentiated liposarcomas (DDLS) may arise from well-differentiated subtypes (WDLS) upon disease progression, however, this key issue is unresolved due in large part to knowledge gaps about liposarcoma cellular composition. Here, we wished to improve insights into liposarcoma cellular hierarchy. Tumor section analysis indicated that the populations, distinguishable based on expression of CD34 (a marker of adipocyte progenitors) and CD36 (a marker of adipocyte differentiation), occupy distinct intra-tumoral locations in both WDLS and DDLS. Taking advantage of these markers, we separated cells from a panel of fresh human surgical specimens by fluorescence-activated cell sorting (FACS). Based on chromosome analysis and the culture phenotypes of the composing populations, we demonstrate that malignant cells comprise four mesenchymal populations distinguished by expression of CD34 and CD36, while vascular (CD31+) and hematopoietic (CD45+) components are non-neoplastic. Finally, we show that mouse xenografts are derivable from both CD36-negative and CD36-positive DDLS cells, and that each population recreates the heterogeneity of CD36 expression in vivo. Combined, our results show that malignant cells in WDLS and DDLS can be classified according to distinct stages of adipogenesis and indicate immonophenotypic plasticity of malignant liposarcoma cells.

Sex Differences and Bone Metastases of Breast, Lung, and Prostate Cancers: Do Bone Homing Cancers Favor Feminized Bone Marrow?

“…The ER signaling pathways are implicated in disease progression ( 1 , 26 , 28 , 30 , 36 , 37 ), because the ER status of bone metastases usually correlates with the ER status of the primary tumor ( 28 , 36 ). Relatively little is known about the ER signaling pathways that lead to downstream activation of cellular targets that trigger disease progression; however, a protective role is generally suggested from limited clinical evidence: (1) Rabbani, et al demonstrated a decrease in breast cancer cell growth and parathyroid hormone-related protein (PTHrP) production in response to estradiol ( 38 ); (2) in addition, overexpression of ER decreased tumor growth and reduced bone metastasis formation ( 38 ); (3) other studies have shown that kinase inhibitors that were designed to attenuate a host of pathways activated in breast cancer cells are not able to halt disease spread once multiple osseous metastases have appeared ( 16 , 18 , 28 , 36 , 39 ); and (4) a protective role of ERβ in the progression of breast cancer has been suggested, as higher levels of ERβ are predictive of positive response to the ER modulator tamoxifen ( 40 , 41 ). The role of ERβ both in the primary tumor and in bone marrow where metastases occur has only recently become the focus for the development of treatments in addition to those that target ERα ( 40 – 42 ), but may provide an important second index by which to stratify risk in patients with ER positive breast cancers.…”

Stem cells from adipose tissue and breast cancer: hype, risks and hope

“…There is no evidence that ASCs, or MSCs in general, are directly tumorigenic, although liposarcomas contain an aggressive multipotent malignant population resembling ASCs ( Zhang et al , 2013 ). However, a body of data indicates that these cells may acquire a tumour-supporting function.…”

Hypothesis: The Intratumoral Immune Response against a Cancer Progenitor Cell Impacts the Development of Well-Differentiated versus Dedifferentiated Disease in Liposarcoma

“…In xenograft mouse models, both Smith et al and Peng et al have independently confirmed that DD but not WD tumors have the potential to engraft successfully ( 22 , 24 ). As a likely explanation, the highest percentage of CD34-positive stem cells is seen in DD tumors compared to WD and normal fat ( 25 ).…”