bims-stacyt 2022-08-14 papers

Cancer Metastasis Rev. 2022 Aug 08.

The adipocyte microenvironment and cancer.

Abir Mukherjee, Agnes J Bilecz, Ernst Lengyel.

Many epithelial tumors grow in the vicinity of or metastasize to adipose tissue. As tumors develop, crosstalk between adipose tissue and cancer cells leads to changes in adipocyte function and paracrine signaling, promoting a microenvironment that supports tumor growth. Over the last decade, it became clear that tumor cells co-opt adipocytes in the tumor microenvironment, converting them into cancer-associated adipocytes (CAA). As adipocytes and cancer cells engage, a metabolic symbiosis ensues that is driven by bi-directional signaling. Many cancers (colon, breast, prostate, lung, ovarian cancer, and hematologic malignancies) stimulate lipolysis in adipocytes, followed by the uptake of fatty acids (FA) from the surrounding adipose tissue. The FA enters the cancer cell through specific fatty acid receptors and binding proteins (e.g., CD36, FATP1) and are used for membrane synthesis, energy metabolism (β-oxidation), or lipid-derived cell signaling molecules (derivatives of arachidonic and linolenic acid). Therefore, blocking adipocyte-derived lipid uptake or lipid-associated metabolic pathways in cancer cells, either with a single agent or in combination with standard of care chemotherapy, might prove to be an effective strategy against cancers that grow in lipid-rich tumor microenvironments.

Keywords: Adipose tissue; Cancer; Immune cells; Lipids; Metabolism; Metastasis

DOI: https://doi.org/10.1007/s10555-022-10059-x

Cells. 2022 Aug 03. pii: 2388. [Epub ahead of print]11(15):

Adipocyte-Derived Extracellular Vesicles Promote Prostate Cancer Cell Aggressiveness by Enabling Multiple Phenotypic and Metabolic Changes.

Fabrizio Fontana, Martina Anselmi, Emanuela Carollo, Patrizia Sartori, Patrizia Procacci, David Carter, Patrizia Limonta.

BACKGROUND: In recent decades, obesity has widely emerged as an important risk factor for prostate cancer (PCa). Adipose tissue and PCa cells have been shown to orchestrate a complex interaction network to support tumor growth and evolution; nonetheless, the study of this communication has only been focused on soluble factors, although increasing evidence highlights the key role of extracellular vesicles (EVs) in the modulation of tumor progression.
METHODS AND RESULTS: In the present study, we found that EVs derived from 3T3-L1 adipocytes could affect PC3 and DU145 PCa cell traits, inducing increased proliferation, migration and invasion. Furthermore, conditioning of both PCa cell lines with adipocyte-released EVs resulted in lower sensitivity to docetaxel, with reduced phosphatidylserine externalization and decreased caspase 3 and PARP cleavage. In particular, these alterations were paralleled by an Akt/HIF-1α axis-related Warburg effect, characterized by enhanced glucose consumption, lactate release and ATP production.
CONCLUSIONS: Collectively, these findings demonstrate that EV-mediated crosstalk exists between adipocytes and PCa, driving tumor aggressiveness.

Keywords: Warburg effect; adipocytes; chemoresistance; extracellular vesicles; metastasis; obesity; prostate cancer

DOI: https://doi.org/10.3390/cells11152388

Nat Commun. 2022 Aug 08. 13(1): 4633

Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer.

Andre Lima Queiroz, Ezequiel Dantas, Shakti Ramsamooj, Anirudh Murthy, Mujmmail Ahmed, Elizabeth R M Zunica, Roger J Liang, Jessica Murphy, Corey D Holman, Curtis J Bare, Gregory Ghahramani, Zhidan Wu, David E Cohen, John P Kirwan, Lewis C Cantley, Christopher L Axelrod, Marcus D Goncalves.

Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.

DOI: https://doi.org/10.1038/s41467-022-32135-0