**2. Cross-Talk between TGF-**β **and Other Signaling Pathways Mediating EMT**

The signaling pathways cross-talk to form complex networks. Due to several cellular processes like apoptosis, differentiation, proliferation, and homeostasis, the Transforming growth factor β (TGF-β) cross-talk with various other signaling pathways during the EMT process (Figure 2) [21,22]. One of the mechanisms in which Akt activation and the phosphatase and tensin homolog (PTEN) dissociation from β-catenin are mainly responsible for the TGF-β mediated EMT process, where the displacement of β-catenin from adherent junctions occurs [23]. The other signaling pathway that cross-talks with TGF-β is Notch; Notch synergizes with TGF-β signals to enhance/inhibit its signaling activity depending on the input signal [21]. TGF-β signals activate the migration and inhibit the cell proliferation of endothelial cells. However, the Notch signals block the migration of bone morphogenetic protein (BMP) [24]. BMP stimulates the cell migration of endothelial cells; however, in the presence of Notch signaling, the migratory potential gets inhibited [24].

Interestingly, Notch signaling plays a crucial cross-talk in regulating migration by inducing gene expression. Notch dominates the BMP signaling; when the cell-to-cell contact is not there, endothelial cells are not in contact with the nearby cells to migrate until the new cell-to-cell attachment is set [21,24]. The TGF-β requires Notch signaling for the growth arrest in the epithelium; over thirty percent of the genes induced by TGF-β require Notch signaling [25]. The classy EMT marker, the TGF-β, also cross-talks with several other signaling pathways like Extracellular signal-regulating kinase (Erk), c-Jun N-terminal kinase (JNK), and p38. Erk, JNK, and p38 are indirectly regulating the TGF-β during EMT. However, TGF-β activates MAPK and Erk1/2 signaling pathways [26]. The cross-talk of TGF-β versus EGF signaling is the reason for activating Smad-dependent signaling and MAPK-mediated Erk1/2 [27]. The nuclear translocation of MAPK mediated by TGF-β is downregulated by the MAPK-Erk pathway that mediates nuclear exclusion and phosphorylation of Smad-2/3 [27]. During the initiation of EMT, the Akt and PTEN are also regulated by TGF-β. In addition, TGF-β cross-talk with ErbB signaling during the EMT development of breast cancer [28]. The TGF-β also regulates the phosphoinositide 3-kinase (PI3k)-Akt signaling pathways. Akt's activity increases due to the induction of TGF-β-mediated functional activities like cell migration, epithelial to mesenchymal shift, cell survival, and cell growth [27–29]. Human epidermal growth factor receptor 2 (HER2)/RAS opposes the TGF-β-induced programmed cell death and cell arrest; however, it promotes migratory and invasive activities of TGF-β [30]. The EMT-associated cross-talk is validated by pharmacological inhibition of insulin-like growth factor-1R (IGF-1R), which prevents TGF-β-mediated EMT protein signatures [31]. The cross-talk of different pathways involved in EMT is demonstrated in Figure 2.

**Figure 2.** Illustrates the different pathways involved in initiating epithelial-mesenchymal transition (EMT) [32].

#### **3. Natural Chemical Agents as Potential Leads against Cancer**

Among approved chemotherapeutic medications, 80% are bioactive natural compounds [33,34]. 70% of disease conditions, including cancer, are treated with the help of natural products [35]. The natural compounds induce cytotoxicity by targeting various oncogenic signaling [36]. Several marine-derived metabolites show anti-cancer activity in preclinical and clinical settings [37]. Marine-derived compounds include sulfated polysaccharides, sterols, carotenoids, and chitosan. Sulfated polysaccharides and carotenoids have effectively worked against cancer, acquired immune deficiency syndrome (AIDS), CVDs, and other acute and chronic disorders [35]. Various effective marine-derived compounds are summarized in Table 1. Plants, bacteria, animals, insects, and marine life are some of the key sources of natural chemicals with pharmacological and cytotoxic actions such as anti-proliferative, anti-angiogenic, apoptosis-generating, necrosis-inducing, and

anti-inflammatory [38]. Secondary metabolites (Alkaloids, tannins, saponins, flavonoids, steroids) are molecules produced by plants at very minute levels that are therapeutically beneficial in various illnesses [39]. Animals and insects are also rich suppliers of enzymes with various pharmacological applications. Researchers have recently focused on natural substances to investigate their possible use in cancer treatment with lesser side effects. Still, they have only identified a few molecules with clinical efficacy demonstrated in Table 2 [40]. Compounds with anti-proliferative, anti-inflammatory, anti-angiogenic, and apoptotic-inducing properties can treat cancer and reduce the side effects of conventional cancer chemotherapy. They also have a high potential for future use as anti-cancer drugs.

Natural products can offer new hope in fighting EMT and increase therapeutic options worldwide. Drugs of natural origin, like traditional and Chinese medicine, are currently being investigated for various ailments [41]. The cost-effectiveness and richness of good therapeutic efficacy and safety were natural compounds' true and popular features, considering them promising candidates against cancer [42]. The drugs against cancer at present share 1/3rd position share against cancer, meaning it is important to investigate more drugs from the natural origin against cancer [43]. Natural compounds have a high level of rigidity, enhancing the protein cross-talk more than synthetic drugs. They have diversity and versatile structure complexity, a unique natural feature making them the right candidates against cancer [43,44]. The signaling pathways that are responsible for cancer cell survival and TME maintenance are being halted by many natural compounds. The natural compounds have a comprehensive role in inhibiting tumor progression by blocking the survival pathways involved in EMT [9]. Many drugs have been used along with natural compounds, producing efficacious outcomes like decreasing drug resistance and toxicity [42,45]. Natural products can remold the TME [41]. Here we will show various candidates of natural origin demonstrating pharmacological activities against EMT and its associated factors.


**Table 1.** Marine and plants-derived compounds for anti-cancer activity.
