Resveratrol Loaded Liposomes Disrupt Cancer Associated Fibroblast Communications within the Tumor Microenvironment to Inhibit Colorectal Cancer Aggressiveness

Abstract

Colorectal cancer (CRC) is a cancer-associated fibroblast, CAF-rich tumor. CAF promotes cancer cell proliferation, metastasis, drug resistance via secretes soluble factors, and extracellular matrices which leads to dense stroma, a major barrier for drug delivery. Resveratrol (RES) is a polyphenolic compound, has several pharmacologic functions including anti-inflammation and anticancer effects. Considering tumor microenvironment of CRC, resveratrol-loaded liposome (L-RES) was synthesized and employed to inhibit CAF functions. The L-RES was synthesized by thin-film hydration method. The cytotoxicity of L-RES was evaluated using MTT assay. Effect of L-RES treated CAF on tumor spheroid growth was performed. Cell invasion was determined using spheroid invasion assay. The effect of L-RES on 5-fluorouracil (5-FU) sensitivity of CRC cells was determined in co-cultured tumor spheroids. Subtoxic dose of L-RES was selected to study possible inhibiting CAF functions. Decreased CAF markers, α-SMA and IL-6 levels, were observed in L-RES treated activated fibroblast. Interestingly, the activated fibroblast promoted invasive ability and drug resistance of CRC cells in co-culture condition of both 2D and 3D cultures and was attenuated by L-RES treatment in the activated fibroblast. Therefore, L-RES provides a promising drug delivery strategy for CRC treatment by disrupting the crosstalk between CRC cells and CAF.

Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

“…Besides, resveratrol (RES) can also suppress EMT through TGF-β1/Smads signaling in CRC [ 383 ]. Intriguingly, resveratrol-loaded liposome (L-RES) reduced α-SMA and IL-6 levels in activated fibroblasts and disrupted crosstalk between CRC cells and CAF to inhibit the function of CAF [ 384 ]. The anti-tumor role of RES was also observed in BC, LC, and PCa [ 385 – 387 ].…”

Exploring the multimodal health‐promoting properties of resveratrol: A comprehensive review

“…However, the pH 6.8 condition resulted in a significantly longer release than the pH 7.4 condition. According to this outcome, the liposomal formulation of RESV is useful in an acidic environment within the microenvironment compartment of the tumor (Dana et al., 2022 ).…”

Three-dimensional heterotypic colorectal cancer spheroid models for evaluation of drug response

“…Scale bar = 200 µm. (B) Brightfield images of monoculture and heterotypic HT29 spheroids treated with different concentrations of 5-FU for 48 h. Heterotypic spheroids consisted of HT29 spheroids co-cultured with (2 x 10 5 ) activated MRC-5 fibroblasts ( 70 ). Scale bar = 500 µm.…”

“…Consequently, researchers can use 3D CRC spheroid models to test therapeutic strategies modulating CAFs (alone or in combination) as done by Dana et al. ( 70 ) ( Figure 2B ). They demonstrated resveratrol-loaded liposomes (L-RES) therapeutic efficacy in reducing fibroblast activation and increasing drug sensitivity of co-culture spheroid during 5-FU treatment.…”

“…The co-culture spheroids were formed with HT29 colorectal adenocarcinoma cell line and human lung fibroblasts MRC-5 cultured for 3 days in 96 well round bottom ultra-low attachment plates. For the drug sensitivity assay, the co-culture CRC spheroids were treated with 25 μM of L-RES in combination with 5-FU at concentrations of 5–25 μM for 2 more days ( 70 ).…”