TRAIL-Sensitizing Effects of Flavonoids in Cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major hurdle, thus limiting the use of TRAIL as a single agent. Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated in resistant tumors by combined treatment with antitumor agents, ranging from synthetic molecules to natural products. Among the latter, flavonoids, the most prevalent polyphenols in plants, have shown remarkable competence in improving TRAIL-driven apoptosis in resistant cell lines as well as tumor-bearing mice with minimal side effects. Here, we summarize the molecular mechanisms, such as the upregulation of death receptor (DR)4 and DR5 and downregulation of key anti-apoptotic proteins [e.g., cellular FLICE-inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), survivin], underlying the TRAIL-sensitizing properties of different classes of flavonoids (e.g., flavones, flavonols, isoflavones, chalcones, prenylflavonoids). Finally, we discuss limitations, mainly related to bioavailability issues, and future perspectives regarding the clinical use of flavonoids as adjuvant agents in TRAIL-based therapies.

Impact of Western Diet and Ultra-Processed Food on the Intestinal Mucus Barrier.

The intestinal epithelial barrier plays a key role in the absorption of nutrients and water, in the regulation of the interactions between luminal contents and the underlying immune cells, and in the defense against enteric pathogens. Additionally, the intestinal mucus layer provides further protection due to mucin secretion and maturation by goblet cells, thus representing a crucial player in maintaining intestinal homeostasis. However, environmental factors, such as dietary products, can disrupt this equilibrium, leading to the development of inflammatory intestinal disorders. In particular, ultra-processed food, which is broadly present in the Western diet and includes dietary components containing food additives and/or undergoing multiple industrial processes (such as dry heating cooking), was shown to negatively impact intestinal health. In this review, we summarize and discuss current knowledge on the impact of a Western diet and, in particular, ultra-processed food on the mucus barrier and goblet cell function, as well as potential therapeutic approaches to maintain and restore the mucus layer under pathological conditions.

Anthelmintic Drugs as Emerging Immune Modulators in Cancer.

Despite recent advances in treatment approaches, cancer is still one of the leading causes of death worldwide. Restoration of tumor immune surveillance represents a valid strategy to overcome the acquired resistance and cytotoxicity of conventional therapies in oncology and immunotherapeutic drugs, such as immune checkpoint inhibitors and immunogenic cell death inducers, and has substantially progressed the treatment of several malignancies and improved the clinical management of advanced disease. Unfortunately, because of tumor-intrinsic and/or -extrinsic mechanisms for escaping immune surveillance, only a fraction of patients clinically respond to and benefit from cancer immunotherapy. Accumulating evidence derived from studies of drug repositioning, that is, the strategy to identify new uses for approved or investigational drugs that are outside the scope of the original medical indication, has suggested that some anthelmintic drugs, in addition to their antineoplastic effects, exert important immunomodulatory actions on specific subsets of immune cell and related pathways. In this review, we report and discuss current knowledge on the impact of anthelmintic drugs on host immunity and their potential implication in cancer immunotherapy.

Targeted Therapy of Interleukin-34 as a Promising Approach to Overcome Cancer Therapy Resistance.

Chemotherapy and immunotherapy have markedly improved the management of several malignancies. However, not all cancer patients respond primarily to such therapies, and others can become resistant during treatment. Thus, identification of the factors/mechanisms underlying cancer resistance to such treatments could help develop novel effective therapeutic compounds. Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) are major components of the suppressive tumor microenvironment and are critical drivers of immunosuppression, creating a tumor-promoting and drug-resistant niche. In this regard, therapeutic strategies to tackle immunosuppressive cells are an interesting option to increase anti-tumor immune responses and overcome the occurrence of drug resistance. Accumulating evidence indicates that interleukin-34 (IL-34), a cytokine produced by cancer cells, and/or TAMs act as a linker between induction of a tumor-associated immunosuppressive microenvironment and drug resistance. In this article, we review the current data supporting the role of IL-34 in the differentiation/function of immune suppressive cells and, hence, in the mechanisms leading to therapeutic resistance in various cancers.

Smad7 Sustains Stat3 Expression and Signaling in Colon Cancer Cells.

Colorectal cancer (CRC) cells contain elevated levels of active signal transducer and the activator of transcription (Stat)-3, which exerts proliferative and anti-apoptotic effects. Various molecules produced in the CRC tissue can activate Stat3, but the mechanisms that amplify such an activation are yet to be determined. In this paper, we assessed whether Smad7, an inhibitor of Transforiming Growth Factor (TGF)-ß1 activity, sustains Stat3 expression/activation in CRC cells. Both Smad7 and phosphorylated (p)/activated-Stat3 were more expressed in the tumoral areas of CRC patients, compared to the normal adjacent colonic mucosa of the same patients, and were co-localized in primary CRC cells and CRC cell lines. The knockdown of Smad7 with a Smad7 antisense oligonucleotide (AS) reduced p-Stat3 in both unstimulated and interleukin (IL)-6- and IL-22-stimulated DLD-1 and HCT116 cells. Consistently, reduced levels of BCL-xL and survivin, two downstream signaling targets of Stat3 activation, were seen in Smad7 AS-treated cells. An analysis of the mechanisms underlying Smad7 AS-induced Stat3 inactivation revealed that Smad7 AS reduced Stat3 RNA and protein expression. A chromatin immunoprecipitation assay showed the direct regulatory effect of Smad7 on the Stat3 promoter. RNA-sequencing data from the Tumor, Normal and Metastatic (TNM) plot database showed a positive correlation between Smad7 and Stat3 in 1450 CRC samples. To our knowledge, this is the first evidence supporting the theory that Smad7 positively regulates Stat3 function in CRC.

Rafoxanide sensitizes colorectal cancer cells to TRAIL-mediated apoptosis.

Colorectal cancer (CRC) remains a leading causes of cancer-related death in the world, mainly due to the lack of effective treatment of advanced disease. TNF-related apoptosis-inducing ligand (TRAIL)-driven cell death, a crucial event in the control of tumor growth, selectively targets malignant rather than non-transformed cells. However, the fact that cancer cells, including CRC cells, are either intrinsically resistant or acquire resistance to TRAIL, represents a major hurdle to the use of TRAIL-based strategies in the clinic. Agents able to overcome CRC cell resistance to TRAIL have thus great therapeutic potential and many researchers are making efforts to identify TRAIL sensitizers. The anthelmintic drug rafoxanide has recently emerged as a potent anti-tumor molecule for different cancer types and we recently reported that rafoxanide restrained the proliferation of CRC cells, but not of normal colonic epithelial cells, both in vitro and in a preclinical model mimicking sporadic CRC. As these findings were linked with the induction of endoplasmic reticulum stress, a phenomenon involved in the regulation of various components of the TRAIL-driven apoptotic pathway, we sought to determine whether rafoxanide could restore the sensitivity of CRC cells to TRAIL. Our data show that rafoxanide acts as a selective TRAIL sensitizer in vitro and in a syngeneic experimental model of CRC, by decreasing the levels of c-FLIP and survivin, two key molecules conferring TRAIL resistance. Collectively, our data suggest that rafoxanide could potentially be deployed as an anti-cancer drug in the combinatorial approaches aimed at overcoming CRC cell resistance to TRAIL-based therapies.

Targeting IL-34/MCSF-1R Axis in Colon Cancer.

Colorectal carcinoma (CRC) is one of the most common neoplasias in the Western world and it is still one of the most deadly cancers worldwide mainly due to the fact that metastatic CRC is not responsive to current pharmacologic treatment. Identification of pathways that sustain CRC cell behaviour could help develop effective therapeutic compounds. A large body of evidence indicates that colon carcinogenesis is a dynamic process in which multiple cell types present in the tumor microenvironment either stimulate or suppress CRC cell growth, survival, and diffusion mainly via the production of cytokines. Interleukin-34 (IL-34), a cytokine initially known for its ability to regulate monocyte/macrophage survival and function, is highly produced in human CRC by both cancer cells and non-tumoral cells. IL-34 function is mainly mediated by interaction with the macrophage colony-stimulating factor-1 receptor (MCSF-1R), which is also over-expressed by CRC cells as well as by tumour-associated macrophages (TAMs) and cancer-associated fibroblasts. IL-34-driven MCSF-1R activation triggers several pro-tumoral functions in the colon. In this article, we review the current understanding of the involvement of IL-34 and its receptor in CRC, with particular attention to the available evidence about the IL-34/MCSF-1R axis-mediated regulation of TAMs and the role of IL-34 and MCSF-1R in promoting cancer resistance to chemotherapy and immunotherapy. Manuscript Contribution to the Field: In this review, we highlight the multiple effects of IL-34 and its receptor, macrophage colony-stimulating factor-1 receptor, on the activity of colorectal cancer (CRC) cells and non-tumoral cells, with particular attention to the available data supporting the role of IL-34/MCSF-1R axis in the control of tumor-associated macrophages. The findings summarized in this manuscript could help understand whether targeting IL-34/MCSF-1R can be exploited for therapeutic intervention in CRC.