Targeting the crosstalk between canonical Wnt/β-catenin and inflammatory signaling cascades: A novel strategy for cancer prevention and therapy

Cancer is a global public health concern. The most prominent tactics currently utilized to combat cancer are surgery, targeted therapy, chemotherapy, and radiotherapy. These treatment strategies have lowered the incidence and cancer associated mortality rate in the past decade (Siegel, Miller, & Jemal, 2019; Trinchieri, 2020). A persistent increase in the count of cancer survivors has been witnessed over the last few years and it has reached approximately 5% of the patients diagnosed with cancer in many nations (de Moor et al., 2013; Guzzinati et al., 2018; Hovaldt et al., 2015; Maddams, Utley, & Møller, 2012). Such a trend is believed to be associated with early diagnosis and improved treatment protocols (Tralongo, Surbone, Serraino, & Dal Maso, 2019).

Several genetic, environmental and other factors are associated with different types of cancer. The majority of cancer cases (approximately 90% of all the cancer cases) are the result of somatic mutations or environmental factors, while the remaining are caused by germline mutations (Tomasetti, Li, & Vogelstein, 2017). A substantial proportion of these risk factors and environmental causes are linked with different forms of chronic inflammation. An estimated 20% of cancers are associated with chronic infections, roughly 30% are linked to inhaled pollutants and tobacco smoking, and 35% are attributed to various dietary factors out of which approximately 20% cancer burden is linked to obesity (Coussens & Werb, 2002; Tralongo et al., 2019).

In last few decades the effect of inflammation and immune system on progression and development of cancer has gained immense attention. Currently, a paradigm shift is being observed in the field of cancer biology. The focus of cancer research has shifted from “cancer cell centric” to a more inclusive phenomenon in which cancer cells are viewed as a part of stromal cell network which consists of vascular cells, fibroblasts and inflammatory immune cells that together conduce a tumor microenvironment (Greten & Grivennikov, 2019). Inflammation is closely associated with different tumor types. For instance, in patients with irritable bowel disease, local and systemic inflammation is a prominent risk factor for tumorigenesis in the gastrointestinal tract (GIT), and up to two out of ten of these aforementioned patients ultimately develop colon cancer (Brennan & Garrett, 2016).

With regards to inflammatory cancers, Wnt signaling pathway has emerged as key player in cancer biology (Paul Polakis, 2012). It was in the early 1980s that initial identification of WNT1 gene was performed through mutagenesis screening in Drosophila melanogaster. Since then several Wnt family members have been identified through subsequent screening of genes (Clevers & Nusse, 2012). The Wnt signaling pathway plays a key role in regulation of several cellular functions which include cell survival, maintenance, proliferation, differentiation, migration, and apoptosis (Makena, Ranjan, Thirumala, & Reddy, 2020; Nusse & Clevers, 2017; Zhan, Rindtorff, & Boutros, 2017). It is vital for the process of embryonic development and homeostasis of numerous tissues, such as GIT (Flanagan et al., 2017, Flanagan et al., 2015), breast, liver, and skin (Nusse & Clevers, 2017). Due to its involvement in several key functions, Wnt dysregulation is associated with various human diseases (Clevers & Nusse, 2012; Kahn, 2014), including gastric, colon, liver and breast cancers (Flanagan, Vincan, & Phesse, 2019; Phesse, Flanagan, & Vincan, 2016).

A crosstalk between inflammatory cascade and Wnt/β-catenin pathway have been established in numerous inflammatory cancers (Li et al., 2019b; Li, Zhao, Qiu, & Ma, 2019a; Ma & Hottiger, 2016; Nejak-Bowen, Kikuchi, & Monga, 2013). Wnt/β-catenin pathway and inflammatory signaling share mutual co-dependence. Very limited comprehensive reviews are available on the co-existence and co-dependence of Wnt/β-catenin signaling and various inflammatory cascades (Suryawanshi, Tadagavadi, Swafford, & Manicassamy, 2016). A review on the crosstalk between Wnt/β-catenin and NF-κB signaling during inflammation (Ma & Hottiger, 2016) is available; however, this work provides limited information on therapeutic targeting of these pathways in cancer. To the best of our knowledge, our present work provides the first comprehensive review focused on the possibility and importance of integrated targeting of the Wnt/β-catenin signaling along with the pro-inflammatory cascades to achieve efficient therapy and prevention of inflammatory cancers. This review focuses on the canonical pathway of Wnt signaling as a lucrative target for therapeutic advances in inflammatory cancer. The review also highlights the use and efficacy of various synthetic and natural products as an emerging approach for modulating Wnt signaling coupled with inflammatory cascades. The review includes a critical analysis of the available scientific evidence that illuminates the crosslink between Wnt/β-catenin signaling and various inflammatory cascades in inflammatory cancers, especially breast, gastrointestinal, endometrial, and ovarian cancer. Further, the review highlights the experimental findings on numerous synthetic and natural compounds that target the crosslink between Wnt/β-catenin pathway and inflammatory mediators to achieve cancer prevention and intervention. Finally, we discuss the current challenges, limitations, and future directions of the research.