Targeting of the Peritumoral Adipose Tissue Microenvironment as an Innovative Antitumor Therapeutic Strategy

Background Colorectal cancer (CRC) is the third most common malignancy worldwide. CRC cells are situated in an adipocyte-rich microenvironment, which leads to interactions between adipocytes and CRC cells. Upon exposure to cancer cells, adipocytes transform into cancer-associated adipocytes (CAAs), and as a result, they gain features that promote tumor progression. The aim of this research was to shed more light on the detailed role of interactions between adipocytes and CRC cells associated with cancer progression in the context of these alterations. Methods To implement adipocyte-CRC cell interaction, a co-culture model was applied. The analyses mainly focused on the metabolic modifications within CAAs and CRC cells, as well as the proliferation and migration potential of CRC cells. The impact of CRC on adipocytes was investigated by qRT-PCR analysis and Oil Red O staining. Proliferation and migration of CRC cells upon co-culture were tested with videomicroscopy, XTT, and a wound healing assay. Metabolic changes within CAAs and CRC cells were investigated based on lipid droplet formation, cell cycle analysis, gene and protein expression by qRT-PCR, and western blotting techniques. Results CRC cells induced reprogramming of adipocytes into CAAs, which was connected with downregulation of lipid droplet formation in CAAs and alteration in adipocyte features. CAAs showed decreased metabolism-related gene expression, phosphorylation of Akt, ERK kinases, STAT3, and lactate secretion in comparison to the control. CAAs also promoted the migration, proliferation, and lipid droplet accumulation of CRC cells. After co-culturing with adipocytes, there was a shift to the G2/M phase of the cell cycle according to the differences in cyclin expression. Conclusion There are complex bidirectional interactions between adipocytes and CRC cells that may be connected with the induction of CRC cell progression.

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Mutual impact of adipocytes and colorectal cancer cells growing in co-culture conditions

Olszańska

Pietraszek-Gremplewicz

Domagalski

et al. 2023

Cell Commun Signal

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The Adipocyte–Macrophage Relationship in Cancer: A Potential Target for Antioxidant Therapy

et al. 2023

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Obesity has emerged as a major public health concern with a staggering 39% worldwide prevalence as of 2021. Given the magnitude of the problem and considering its association with chronic low-grade systemic inflammation, it does not come as a surprise that obesity is now considered one of the major risk factors for the development of several chronic diseases, such as diabetes, cardiovascular problems, and cancer. Adipose tissue dysfunction in obesity has taken center stage in understanding how changes in its components, particularly adipocytes and macrophages, participate in such processes. In this review, we will initially focus on how changes in adipose tissue upon excess fat accumulation generate endocrine signals that promote cancer development. Moreover, the tumor microenvironment or stroma, which is also critical in cancer development, contains macrophages and adipocytes, which, in reciprocal paracrine communication with cancer cells, generate relevant signals. We will discuss how paracrine signaling in the tumor microenvironment between cancer cells, macrophages, and adipocytes favors cancer development and progression. Finally, as reactive oxygen species participate in many of these signaling pathways, we will summarize the information available on how antioxidants can limit the effects of endocrine and paracrine signaling due to dysfunctional adipose tissue components in obesity.

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Multi-Faceted Role of Cancer-Associated Adipocytes in Colorectal Cancer

Grigoraș,

Amalinei

2023

Biomedicines

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Colorectal cancer (CRC) is one of the most commonly diagnosed types of cancer, especially in obese patients, and the second cause of cancer-related death worldwide. Based on these data, extensive research has been performed over the last decades to decipher the pivotal role of the tumor microenvironment (TME) and its cellular and molecular components in CRC development and progression. In this regard, substantial progress has been made in the identification of cancer-associated adipocytes’ (CAAs) characteristics, considering their active role in the CCR tumor niche, by releasing a panel of metabolites, growth factors, and inflammatory adipokines, which assist the cancer cells’ development. Disposed in the tumor invasion front, CAAs exhibit a fibroblastic-like phenotype and establish a bidirectional molecular dialogue with colorectal tumor cells, which leads to functional changes in both cell types and contributes to tumor progression. CAAs also modulate the antitumor immune cells’ response and promote metabolic reprogramming and chemotherapeutic resistance in colon cancer cells. This review aims to report recent cumulative data regarding the molecular mechanisms of CAAs’ differentiation and their activity spectrum in the TME of CRC. A better understanding of CAAs and the molecular interplay between CAAs and tumor cells will provide insights into tumor biology and may open the perspective of new therapeutic opportunities in CRC patients.

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Targeting of the Peritumoral Adipose Tissue Microenvironment as an Innovative Antitumor Therapeutic Strategy

Cited by 3 publications

References 160 publications

Mutual impact of adipocytes and colorectal cancer cells growing in co-culture conditions

Mutual impact of adipocytes and colorectal cancer cells growing in co-culture conditions

The Adipocyte–Macrophage Relationship in Cancer: A Potential Target for Antioxidant Therapy

Multi-Faceted Role of Cancer-Associated Adipocytes in Colorectal Cancer

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