**1. Introduction**

Cancer is the leading cause of death globally [1]. According to the global demographic characteristics, it is expected to increase by approximately >20 million by 2025 [2]. The treatment paradigm improved in the past decade with the advancement in cancer research. Breast cancer (BC), colorectal cancer (CRC), lung cancer (LC), and prostate cancer (PC) are the most common types of cancers [1,3]. Various cellular pathways are involved in cancer development and progression. Several drug candidates are approved to target these pathways for their management [4]. One reason behind drug resistance is the process of Epithelial-mesenchymal transition (EMT) involved in cancer progression. EMT is an extremely regulated physiological process that has a significant role in tissue repair and embryogenesis [5]. During EMT, the cells undergo multiple morphologic, biological, and

**Citation:** Anwar, S.; Malik, J.A.; Ahmed, S.; Kameshwar, V.A.; Alanazi, J.; Alamri, A.; Ahemad, N. Can Natural Products Targeting EMT Serve as the Future Anticancer Therapeutics? *Molecules* **2022**, *27*, 7668. https://doi.org/10.3390/ molecules27227668

Academic Editors: Alessandra Ammazzalorso, Barbara De Filippis and Marialuigia Fantacuzzi

Received: 4 October 2022 Accepted: 1 November 2022 Published: 8 November 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

genetic rearrangements, leading to their mesenchymal phenotypes [6]. EMT is pathologically associated with fibrosis and cancer, leading to their progression. EMT has been linked to the formation of invasive and cancer stem cells in carcinomas [7].

EMT is initiated by EMT activating transcription factors (EMT-TFs), including SNAIL (SNAI1) and SLUG (SNAI2), the basic helix–loop–helix factors TWIST1 and TWIST2. As proven for SNAIL, TWIST, Zinc figure E-box binding homeobox 1 (ZEB1), and Zinc figure E-box binding homeobox 2 (ZEB2), these features can repress epithelial genes like the E-cadherin-producing CDH1 by binding to E-Box in their cognate promoter regions. Simultaneously, EMT-TFs activate genes associated with a mesenchymal phenotype, such as Vimentin (VIM), Fibronectin 1 (FN1), and N-Cadherin (CDH2). Several activities, however, are not common and are carried out by separate EMT- transcription factors (TFs) due to differences in coding sequences or protein size and structure [8]. An overview of the EMT pathway is shown in Figure 1. In other words, EMT is a biotic mechanism in which epithelial cells become polarized.

**Figure 1.** Hypoxia, growth factor, cytokines, and ECM activate the pathways that can trigger the EMT by activating EMT transcription factors (EMT-TFs), including SNAIL, SLUG, and the basic helix–loop– helix factors TWIST. As proven for SNAIL, TWIST, Zinc figure E-box binding homeobox 1 (ZEB1), and ZEB2, these features can repress epithelial genes like the E-cadherin-producing CDH1 by binding to E-Box in their cognate promoter regions. Simultaneously, EMT-TFs activate genes associated with a mesenchymal phenotype, such as Vimentin (VIM), Fibronectin 1 (FN1), and N-Cadherin (CDH2), etc. [8].

The heterogeneous mixture of cells like fibroblasts, endothelial cells, noncellular constituents, immune cells, extracellular matrix, cytokines, growth factors, and basement membrane is known as a tumor microenvironment (TME) [9]. EMT is essential for developing and initiating tumors and their recurrence and progression. In TME, the most abundant cells are cancer-associated fibroblasts (CAFs), which cross-talk with tumor cells, extracellular matrix (ECM), immune cells, and endothelial cells for cancer progression [9–13]. Several therapeutic agents are now being designed to target these CAFs [12,14]. Many natural

agents have been identified to target CAF by altering the key signaling pathways, epigenetics, kinases, and enzymes. Targeting CAFs and altering the pathways affect cancer-stroma association in TME, resulting in decreased cancer progression. The natural compounds might have promised anti-cancer activity and are worth investigating against different tumors. The characteristic feature of carcinogenesis is ECM stiffness that supports the tumor cells. The crosslinking of ECM components like collagen with the tumor cells occurs via CAFs [15]. LOX-lysyl oxidase, the enzyme highly overexpressed in tumors derived from CAFs, acts as a collagen crosslinking initiator in several cancers like breast and gastric cancers, ultimately enhancing EMT, cell survival, invasion, drug resistance, and angiogenesis [16]. The ECM degrading enzymes like matrix metalloproteases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) inhibitors are altered by CAFs during angiogenesis and invasion, causing modulation of TME. The MMP2 and 9 are well investigated and highly associated with cancer growth and development [17,18]. The enzymes like metalloproteinases and disintegrin, associated with the MMPs super-family, are increased by CAFs, promoting cancer progression [19]. The CAFs also apply physical forces to pull out the epithelial basement membrane, causing the promotion of EMT in enzyme independent manner [20]. The CAFs promote EMT remolding and are promising therapeutic targets in halting EMT to prevent cancer metastasis. Natural compounds have proven to be the best alternatives to the current therapies against cancer. Many noteworthy examples are in front of us, where natural compounds have proven better than existing standard therapies against different ailments, such as cancer or infectious diseases. It is worth investigating the potential of natural compounds, whether from the marine, plant, or animal, against different types of cancers to find the solution for the growing deadly ailment in the world. Due to growing concerns regarding cancer metastasis, most therapies fail to cure, and the patients suffer greatly due to high toxicity. Cancer resistance is another challenge against current therapies, making cancer more complicated to manage. The natural compounds could be a game changer as anti-cancer therapy that specifically targets the EMT process and halts the process of cancer progression.
