Open access peer-reviewed chapter

Recent Progress on the Molecular Mechanisms of Anti-invasive and Metastatic Chinese Medicines for Cancer Therapy

Written By

Wei Guo, Ning Wang and Yibin Feng

Submitted: November 14th, 2016 Reviewed: April 5th, 2017 Published: July 12th, 2017

DOI: 10.5772/intechopen.69017

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Abstract

Despite of the recent advances in diagnostic and therapeutic approaches, cancer remains as the leading cause of death worldly with diverse causal factors regarding genes and environment. Invasion and metastasis, as one of the most important hallmarks for cancer, have restrained the successful clinical therapy and are the primary causes of death among cancer patients. So far, most chemotherapeutic drugs are not effective for metastatic cancer due to drug resistance and serious side effects. Therefore, it is urgently essential to develop more effective therapeutic methods. Owing to their diverse biological activities and low toxicity, naturally active compounds derived from Chinese medicines, as a complementary and alternative approach, are reported to promote the therapeutic index and provoked as an excellent source for candidates of anti-metastatic drugs. With the rapid development of molecular biology techniques, the molecular mechanisms of the effects of potential anti-invasive and metastatic Chinese medicines are gradually elucidated. This chapter reviews the potential anti-invasive and metastatic mechanisms of naturally active compounds from Chinese medicines, including suppression of EMT, proteases and cancer-induced angiogenesis, anoikis regulation of circulating tumor cells and regulation of miRNA-mediated gene expression, providing scientific evidence for clinically using Chinese medicines in the field of cancer therapy.

Keywords

  • Chinese medicines
  • anti-invasion and metastasis
  • molecular mechanisms
  • cancer therapy

1. Introduction

Despite of all the recent advances in diagnostic and therapeutic approaches, cancer remains the leading cause of death and primary public health hazard all over the world [1, 2]. With diverse causal factors (genetic and environmental, physical, psychological and biochemical factors), cancer has a various disease spectrum to more than a hundred different kinds of malignancies, such as lung cancer, breast cancer, renal carcinoma, hepatocellular carcinoma, and so on [3]. It is a progressive disease with multiple pathological processes covering cancer initiation, development, and metastasis. Cancer is characterized by several key hallmarks [46], namely uncontrolled replication ability of abnormal cells, resistance to programmed cell death, invasion into the surrounding extracellular matrix (ECM), sustained capability of angiogenesis, and metastatic spread to other sites.

As one of the most important hallmarks for cancer, metastasis is an intricate process concerning the following six steps (as shown in Figure 1): (i) detachment of cancer cells through degrading ECM, (ii) local migration and invasion into the surrounding tissues, (iii) intravasation into blood and/or lymphatic vessel systems, (iv) survival and circulation in the circulatory system, (v) extravasation into the targeted secondary organ site, and (vi) multiplication and formation of a secondary tumor [79]. During these steps, the metastatic cancer cells should have special properties to overcome the obstacles, such as the capability of invasion, resistance to anoikis, and angiogenesis. Basically, these steps are regulated by multiple factors, including but not limited to changes of expression of related genes, cytoskeleton remodeling, proteolysis degradation of ECM, and so on [10]. Metastasis is a nonrandom process, and different metastatic cancer types possess their corresponding preferred sites of metastasis. For instance, the preferred sites of breast cancer cells are lung, liver, and bone [11]. Since invasion and metastasis restrain the successful clinical therapy and are the primary causes of death among cancer patients, it has been widely accepted that invasion and metastasis become a highlighted topic of research interests, and active efforts are still needed to understand the underlying molecular mechanisms and develop effective anti-metastatic therapies.

Figure 1.

The process involving in cancer metastasis.

At the present day, there are three conventional therapeutic approaches which are used to treat metastatic cancers, namely surgical resection, chemotherapy, and radiotherapy. Though remain as the main treatment approach for metastatic cancer patients, most chemotherapeutic drugs are not effective for metastatic cancer due to drug resistance and serious side effects. Most chemotherapeutic drugs fail to selectively kill cancer cells without destroying normal cells at the sites of metastasis [12] and thus cause severe toxicity, such as appetite loss, weight loss, insomnia, fatigue, even life threat etc [13, 14]. Although chemotherapeutics significantly leads to regression of the primary tumor, some investigations even report that it may also promote and enhance metastatic formation of a secondary tumor [15, 16]. Besides, metastatic cancers are demonstrated to be largely resistant against chemotherapeutics. Despite that various approaches have been applied to treat metastatic cancers, the clinical outcomes of metastatic cancer treatment are still not at a satisfactory level. Therefore, it is urgently essential to develop more effective therapeutic methods with minimal adverse effects for metastatic cancer treatment.

Traditional medicine, such as Chinese medicine, has been shown to exhibit various pharmacological activities and used in treatment of various diseases in Asian countries and regions for a long time [17]. The numerous natural compounds obtained from Chinese medicines chemically range from flavonoids and polyphenols to mineral salts, which have been reported to be an excellent source for anti-cancer agents [18]. Owing to their long-lasting efficacy, diversity in biological activities, and low toxicity, natural active products from Chinese medicines, including single compounds and various extracts, are being developed for treatment of metastatic cancer [19, 20]. In line with such a concept, several natural active products from Chinese medicines have been currently investigated as a complementary and alternative approach, and their anti-metastatic properties have been focused to find newly discovered mechanisms with the hope to promote the therapeutic index of metastatic cancer.

With the rapid development of molecular biology techniques, the molecular mechanisms underlying the effects of potential anti-invasive and metastatic Chinese medicines are gradually elucidated. Understanding of the underlying molecular mechanisms may in turn lead to the discovery of novel anticancer drugs. In summary, this chapter reviews the anti-invasive and metastatic effect of natural active compounds from Chinese medicines and their molecular mechanisms. Tables 1 and 2 respectively summarized the potential underlying molecular mechanisms of single pure compounds and various extracts from Chinese medicines to suppress cancer invasion and metastasis.

Single pure compoundCancer typeStudy typeMechanism of actionsRef. (PMID)
ArctigeninBreast cancerIn vitro MCF-7 and MDA-MB-231 cellsSuppress MMP-9 and uPA28035371
Colorectal cancerIn vitro CT26, MC38, CCD-18Co and SW620 cells and in vivo BALB/c female miceInduce anoikis via MAPKs signaling, inhibit EMT through increasing E-cadherin and decreasing N-cadherin, vimentin, β-catenin, and Snail and downregulate MMP-2/927618887
Astragaloside IVBreast cancerIn vitro MDA-MB-231 cells and in vivo athymic Balb/c nude miceDownregulate Vav3 and MMP-2/927930970
BerberineHepatocellular carcinomaIn vitro MHCC-97L, Bel-7402, SMMC-7721 cells and in vivo nude miceDownregulate uPA and suppress Id-1 via HIF-1α/VEGF pathway27092498
25496992
Nasopharyngeal carcinomaIn vitro HONE1 cellsSuppress Rho GTPases including RhoA, Cdc42, and Rac119513545
Notoginsenoside R1Colorectal cancerIn vitro HCT-116 cellsReduce MMP-9, integrin-1, E-selectin and ICAM-1 expressions27840961
MatrineProstate cancerIn vitro DU145 and PC-3 and male Balb/c nude mice inoculated subcutaneously with cellsDownregulate MMP-2/928000853
Bibenzyl 4,5,4′-trihydroxy-3,3′- dimethoxybibenzylLung cancerIn vitro H292 cellsSuppress EMT markers (vimentin and Snail) and increase the level of E-cadherin and induce anoikis by reduction of activated protein kinase B (p-AKT) and activated extracellular signal-regulated kinase (p-ERK)24692728
CurcuminLung cancerIn vitro H460 cellsSensitize anoikis by down-regulating Bcl-220127174
ImperatorinLung cancerIn vitro H23, H292 and A549 cellsSensitize anoikis by down-regulating Mcl-1 protein and up-regulating Bax23108812
Artonin ELung cancerIn vitro H460, A549 and H292 cellsSensitize anoikis by down-regulating Mcl-1 protein23225436
Ecteinascidin 770Lung cancerIn vitro H23 and H460 cellsSensitize anoikis by down-regulating Mcl-1 protein and up-regulating Bax23393342
Renieramycin MLung cancerIn vitro H460 cellsSensitize anoikis by down-regulating survival proteins p-ERK and p-AKT and anti-apoptotic proteins BCL2 and MCL127069144
Oroxylin ALung cancerIn vitro A549 cells and in vivo nude miceSensitize anoikis by inactivating the c-Src/AKT/HK II pathway23500080
GeraniinLung cancerIn vitro A549 cellsInhibit the TGF-β1-induced EMT26169124
GenipinHepatocellular carcinomaIn vitro HepG2 and MHCC97L cells and in vivo male nude miceOverexpress TIMP-1 and inhibit MMP-223029478
Kukoamine AGlioblastomaIn vitro C6, U251 and WJ1 cells and in vivo nude mice (BALB/C-nu/nu)Inhibit EMT and induce anoikis by downregulating expressions of C/EBPβ and 5-LOX27824118
GigantolLung cancerIn vitro H460 cellsDecrease EMT markers including N-cadherin, vimentin, and Slug26733180
MoscatilinLung cancerIn vitro H460 cellsInhibit EMT by suppressing mesenchymal cell markers (vimentin, Slug, and Snail) and induce anoikis by survival proteins (ERK and Akt) suppression and Cav-1 down-regulation26384689
2,3,5- Trimethoxy-4-cresolLung cancerIn vitro A549 cellsSuppress Akt, MMP-2 and MMP-9 and increase E-cadherin and TIMP-125951809
DeoxyelephantopinLung cancerIn vitro A549 cellsSuppress MMP-2, MMP-9, uPA, and uPAR25686703
BufalinLung cancerIn vitro NCI-H460 cellsSuppress MMP-2, MMP-9, MAPKs, and NF-kB26446205
Epicatechin-3-gallateLung cancerIn vitro A549 cells and in vivo BALB/c nude miceInhibit the TGF-β1-induced EMT by up-regulating epithelial marker (E-cadherin) and down-regulating mesenchymal markers (fibronectin and p-FAK)27224248
Rocaglamide-AProstate cancer, breast cancer and cervical cancerIn vitro PC-3, MDA- MB-231, HCT116, HeLa, and 293T cellsInhibit the activity of Rho GTPases RhoA, Rac1 and Cdc4227340868
Chamaejasmenin BBreast cancerIn vitro MDA-MB-231, ZR75-1 and 4T1 cells and in vivo BALB/c miceBlock TGF-beta induced EMT27374079
ArtesunateCervical cancerIn vitro CaSki and Hela cellsInhibit HOTAIR and COX-2 expressions27736969
Ginsenoside RdBreast cancerIn vitro 4T1 cells and in vivo BALB/c miceDerepress miR-18a-mediated Smad2 expression27641158
QuercetinColorectal cancerIn vitro CT26 and MC38 cells and in vivo BALB/c female miceInduce apoptosis through the MAPKs pathway, regulate EMT markers including E-, N-cadherin, β-catenin, and snail and regulate MMPs and TIMPs27823633
SulforaphaneLung cancerIn vitro H1299, 95C and 95D cells and in vivo male BALB/c nude miceInhibit EMT by silencing miR-616-5p27890917
TricetinOsteosarcomaIn vitro U2OS and HOS cellsRepress MMP-9 via p38 and Akt pathways27860196
Arsenic trioxideChondrosarcomaIn vitro HCS-2/8, OUMS-27, SW1353, and JJ012 cellsInhibit EMT via the miR-125b/Stat3 axis27576314
Cucurbitacin BBreast cancerIn vitro MDA-MB-231 and 4T1 cellsInhibit angiogenesis via downregulating VEGF/FAK/MMP-9 signaling27210504
2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucosideColorectal cancerIn vitro HT-29 cellsSuppress MMP-2 and ICAM-1 via NF-κB pathway27278328
7,7″-DimethoxyagastisflavoneMelanomaIn vitro B16F10 cells and in vivo female C57BL/6JNarl miceDown-regulate the polymerization of F-actin via Cdc42/Rac1 pathway and inhibit lamellipodia formation via suppressing CREB phosphorylation27487150
NobiletinOsteosarcomaIn vitro U2OS and HOS cellsBlock ERK and JNK-mediated MMPs expression27144433

Table 1.

Summary on the potential underlying molecular mechanisms of single pure compound from Chinese medicines to suppress cancer invasion and metastasis.

Various extractsCancer typeStudy typeMechanism of actionsRef. (PMID)
Ethanol extract of baked Gardeniae FructusMelanomaIn vitro B16F10 and in vivo C57BL/6 miceInhibiting the release of pro-angiogenic factors from tumor cells27779658
Mixture of flavonoids extracted from Korean Citrus aurantiumLung cancerIn vitro A549 cells and in vivo NOD/SCID miceInduce apoptosis through regulating the apoptosis related protein cleaved caspase-3 and p-p53No
Bibenzyl compounds isolated from Dendrobium pulchellumLung cancerIn vitroInduce anoikis23472473
Aqueous extract of Andrographis paniculataEsophageal cancerIn vitro EC-109 and KYSE-520 cellsInhibit anoikis resistance26885447
Methanol extracts of Euphorbia humifusa WilldBreast cancerIn vitro MDA-MB-231 and in vivo Balb/c miceReduce TNFα-induced MMP-9 expression27776550
Ethanol extract of Lophatheri HerbaFibrosarcoma, breast cancer, prostate carcinoma and melanomaIn vitro HT1080, MDA-MB231, DU145, B16F10 cells and in vivo C57BL/6J mice and ICR miceSuppress tumor-induced angiogenesis by decreasing the pro-angiogenic factors27808120
Coptidis Rhizoma aqueous extractHepatocellular carcinomaIn vitro Hep G2 and MHCC97-L cells and in vivo nude miceSuppress Rho/ROCK signaling pathway and inhibit VEGF secretion21106616
24363282
Methanol extracts and butanol extracts of Oldenlandia diffusaBreast cancerIn vitro MCF-7 cellsInhibit PMA-induced MMP-9 and ICAM-1 expressions27876502
Annona muricata leaf aqueous extractBreast cancerIn vitro 4 T1 cells and in vivo female BALB/c miceInduce the apoptosis27558166
Ethanol extract of Siegesbeckia orientalisEndometrial CancerIn vitro RL95-2 and HEC-1AReverse the TGFβ1-induced EMT27527140
Polyphenols of Artemisia annua L.Breast cancerIn vitro MDA-MB-231 cellsSuppress EMT by inhibiting MMP-2/-9 and vascular cell adhesion molecule-127151203
Gegen Qinlian decoctionRenal carcinomaIn vitro ACHN and Caki-1 cells and in vivo male BALB/c nude miceSuppress neoangiogenesis via MMP-2 inhibition25228536

Table 2.

Summary on the potential underlying molecular mechanisms of various extracts from Chinese medicines to suppress cancer invasion and metastasis.

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2. Suppression of epithelial-mesenchymal transition

Recent studies clearly showed that epithelial-mesenchymal transition (EMT) plays an important role in the metastasis of cancers [21]. As the fundamental step during cancer metastasis, EMT is a complex process during which immotile epithelial cells undergo a morphological transformation into motile mesenchymal-appeared cells, triggering cancer cells to detach from the primary site via the loss of cell-to-cell junctions and thus promoting cell migration [22]. There are three different subtypes of EMT, and the third subtype of EMT is associated with the invasion and metastasis of cancers [23]. EMT-phenotypic cells can decrease the level of epithelial marker E-cadherin, a junction protein for cell-cell contact. Besides, they can also increase the level of mesenchymal markers, such as N-cadherin, β-catenin, and vimentin, as well as promote transcription factors of EMT switch, such as Slug and Snail [24, 25]. As EMT has been significantly linked to the metastatic behaviors of cancer cells, natural products obtained from Chinese medicines with the ability to suppress EMT are attracting attention for the development of anti-metastasis therapies.

Among potential natural products, geraniin, a polyphenolic component derived from Phyllanthus amarus, has gained considerable attention over the past decade. Previous study has demonstrated that EMT can be induced by transforming growth factor-beta 1 (TGF-β1) and thus stimulates the migration and invasion of lung adenocarcinoma. Geraniin has been shown to inhibit TGF-β1-induced EMT of lung cancer A549 cells in vitro by inducing the epithelial marker E-cadherin and suppressing Snail and mesenchymal marker N-cadherin and vimentin [26]. A compound derived from Dendrobium ellipsophyllum, bibenzyl 4,5,4′ -trihydroxy-3,3′-dimethoxybibenzyl was shown to inhibit EMT of lung cancer cells via downregulating EMT markers (vimentin and Snail) and upregulating E-cadherin [27]. Such EMT suppression was also observed in lung cancer cells treated with other single compounds obtained from Chinese medicine, such as moscatilin [28], gigantol [29], and epicatechin-3-gallate [30]. A flavonoid obtained from Stellera chamaejasme L., namely chamaejasmenin B, was also reported to block the TGF-β-induced EMT in breast cancer [31]. 5-lipoxygenase (5-LOX) is an enzyme to convert arachidonic acid to leukotrienes [32] and abrogating its expression can inhibit the migration, invasion, and metastasis of cancer cells by suppressing EMT via inactivating E-cadherin and activating snail [33]. CCAAT/enhancer binding protein β (C/EBPβ) was also reported to be related to the migration, invasion, and metastasis of cancer cells by EMT regulation [34]. Kukoamine A, a spermine alkaloid extracted from Cortex lycii radicis, was demonstrated to suppress the migratory and invasive ability of human glioblastoma cell both in vitro and in vivo, and this action was mediated through EMT attenuation via decreasing the levels of 5-LOX and C/EBPβ [35]. Likewise, similar EMT inhibitory effects have also been observed in various extracts from Chinese medicines. Siegesbeckia orientalis Linne is a traditionally used Chinese medicinal herb that exhibits various pharmacological activities. Its ethanol extract (SOE) has been reported as a potential anti-metastatic agent by reversing the TGFβ1-induced EMT via ERK1/2, JNK1/2, and Akt pathways [36]. SOE can inhibit the migration and invasion of endometrial cancer RL95-2 and HEC-1A cells in a dose-dependent manner. Artemisia annua L. is a traditional medicine which has been applied for treating multiple diseases. The polyphenolic compounds from Artemisia annua L. (pKAL) were found to exhibit anti-metastatic property on highly metastatic breast cancer cells MDA-MB-231 [37]. This anti-metastatic property of pKAL was achieved through suppressing EMT by inhibiting MMP-2/-9 and vascular cell adhesion molecule-1 (VCAM-1).

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3. Suppression of proteases expression

Matrix metalloproteinases (MMPs) is regarded as primary factors to trigger metastasis [38]. As extracellular zinc-dependent endopeptidases, they can degrade the basement membrane and ECM and thus play an important role in the migration and invasion of cancers. There are 23 members in MMPs family, among which MMP-2 and MMP-9 are considered to be the key enzymes and play crucial roles in cancer metastasis [39, 40]. The activities of MMPs are finely mediated by tissue inhibitors of metalloproteinases (TIMPs) via their non-covalent binding to the active zinc-binding sites of MMPs [41]. In addition, as a serine-specific protease, urokinase-type plasminogen activator (uPA) can also degrade ECM via binding to uPA receptor (uPAR) and activating plasmin [42]. It is well-known that reorganization of the actin cytoskeleton plays an important role in the migration of cancer cell [43]. This process is mainly regulated by the Rho family GTPases, such as RhoA, Rac1, and Cdc42 via a shuttle between an inactive GDP-bound form and an active GTP-bound form [44, 45]. Since these proteases play an important role in cancer invasion and metastasis via proteolysis, natural products obtained from Chinese medicines with the ability to suppress these proteases are attracting attention for the development of anti-metastasis therapies.

As a phytoestrogen-botanical lignan derived from Arctium lappa, arctigenin was shown to exert its anti-metastatic property through suppressing MMP-9 and uPA of breast cancer cells via inhibiting the upstream signaling pathways including Akt, NF-κB, and MAPK (ERK 1/2 and JNK 1/2), which is dependent to the modulation on estrogen receptor (ER) expression [46]. Such protease regulation was also observed in breast cancer cells treated with astragaloside IV [47]. Notoginsenoside R1 (NGR1) is a primary compound in Panax notoginseng, and its anti-metastatic property has also been revealed [48]. NGR1 can inhibit the migration, invasion, and adhesion of cultured human colorectal cancer cells (HCT-116) via suppressing MMP-9, integrin-1, E-selectin, and ICAM-1 expressions. Such inhibition on colorectal cancer cells was also observed when treated with 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside [49]. As an alkaloid derived from Sophora flavescens, matrine can inhibit the invasion and migration of castration-resistant prostate cancer DU145 and PC3 cells by suppressing MMP-9 and MMP-2 expressions through NF-κB pathway [50]. The phenol derived from Taiwanese edible fungus Antrodia cinnamomea, 2,3,5-trimethoxy-4-cresol, was recently described as an effective anti-metastatic agent against lung cancer via suppressing Akt, MMP-2 and MMP-9, and increasing E-cadherin and TIMP-1[51]. Such protease regulation was also observed in lung cancer cells treated with other single compounds derived from Chinese medicine, such as deoxyelephantopin [52] and bufalin [53]. Genipin, a natural compound obtained from the fruit of Gardenia jasminoides, was reported to exhibit anti-metastatic effect on hepatocellular carcinoma both in cell and animal model. This effect may be related with TIMP-1 overexpression and MMP-2 inhibition of genipin [54]. As an isoquinoline alkaloid isolated from Coptidis rhizome and other medicinal plants, berberine has been shown to exhibit multiple pharmacological actions in treating human diseases, including cancers [55]. Recently, it was reported to inhibit nasopharyngeal carcinoma cell migration and invasion in vitro through suppressing Rho GTPases including RhoA, Rac1, and Cdc42 [56]. The anti-metastatic ability of Rocaglamide-A was also recently described via inhibiting the activity of Rho GTPases RhoA, Rac1, and Cdc42 [57]. As a dietary flavonoid in Eucalyptus honey and Myrtaceae pollen, tricetin was shown to attenuate osteosarcoma cell migration via suppressing MMP-9 via p38 and Akt pathways [58]. Such inhibition on osteosarcoma cells was also observed when treated with nobiletin [59]. The compound obtained from Taxus x media cv. Hicksii, 7,7″-Dimethoxyagastisflavone (DMGF) has been reported to inhibit the invasion and metastasis of melanoma cells in vivo and in vitro [60]. The mechanism study provided evidence that DMGF can downregulate the polymerization of F-actin via Cdc42/Rac1 pathway and inhibit lamellipodia formation via suppressing cAMP response element-binding protein (CREB) phosphorylation. Likewise, similar protease inhibitory effects have also been observed in various extracts from Chinese medicines. The methanol extracts of Euphorbia humifusa Willd was reported to have anti-metastatic effects on breast cancer both in vitro and in vivo via reducing TNFα-induced MMP-9 expression [61]. In addition, the methanol extracts and butanol extracts of Oldenlandia diffusa were also shown to block the metastasis of breast cancer via inhibiting PMA-induced MMP-9 and ICAM-1 expressions [62].

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4. Suppression of cancer-induced angiogenesis

Angiogenesis is a normal physiological process to sprout new vessels during the development of embryogenesis. To the contrary, pathological angiogenesis is associated with multiple diseases including cancers [63]. Highly malignant tumors can induce angiogenesis to provide sufficient oxygen and nutrients for themselves [64]. Additionally, angiogenesis also provides paths for cancer cells to metastasize distant tissues [65]. In tumor microenvironment, tumor and host cells release pro-angiogenic and anti-angiogenic factors. The pro-angiogenic factors include transforming growth factor (TGF), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF), epidermal growth factor (EGF), and so on, and there is a fine balance between them. When the balance is skewed to the pro-angiogenic state, tumor shifts from a dormant state to a hyper-vascularized state [66]. Since angiogenesis plays an important role in the metastatic behaviors of cancer cells, natural products obtained from Chinese medicines targeting on tumor-induced angiogenesis have been regarded as promising agents to metastatic cancers.

Berberine has been shown to exhibit a significant inhibition on the migratory and invasive ability of hepatocellular carcinoma cells. Except for downregulation of uPA, berberine also inhibits angiogenesis through suppressing inhibitor of differentiation/DNA binding (Id-1) via HIF-1α/VEGF pathway [67, 68]. Cucurbitacin B (CuB), a plant triterpenoid, obtained from Cucurbitaceae family has been shown to inhibit the metastasis and angiogenesis of breast cancer MDA-MB-231 and 4T1 cells via downregulating VEGF/FAK/MMP-9 signaling [69]. Recently, a study of artesunate, a normal traditional Chinese medicine, has been conducted to investigate the anti-metastatic effects of artesunate on cervical cancer. The results demonstrated that artesunate inhibits cancer cell migration and invasion in vitro through suppressing HOTAIR and COX-2-mediated angiogenesis [70]. Likewise, similar inhibitory effects have also been observed in various extracts from Chinese medicines. The aqueous extract of Coptidis Rhizoma, a traditional Chinese medicinal herb with a long history, was observed to inhibit hepatocellular carcinoma cell migration both in vitro and in vivo through suppressing Rho/ROCK signaling pathway and inhibiting VEGF secretion [71, 72]. Gardeniae Fructus, a fruit obtained from Gardenia jasminoides Ellis, has been applied as traditional medicine and possesses various health benefits against multiple diseases. A recent study has shown that the ethanol extract of baked Gardeniae Fructus has an inhibitory effect on the angiogenic and metastatic ability of melanoma cells both in vitro and in vivo via inhibiting the release of pro-angiogenic factors [73]. Lophatheri Herba, a dried leaf obtained from Lophatherum gracile Brongn, possesses inhibitory effects on the metastasis and angiogenesis of malignant cancer cells at noncytotoxic doses. It has been shown that ethanol extract of Lophatheri Herba (ELH) can inhibit the cancer cell metastasis both in vitro and in vivo through suppressing tumor-induced angiogenesis via decreasing the pro-angiogenic factors [74]. As an ancient Chinese medicine formula, Gegen Qinlian decoction was reported to suppress the neoangiogenesis in xenografted renal carcinoma cell tumor through inhibiting the enzyme activity of MMP-2 [75].

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5. Anoikis regulation of circulating tumor cells

Anoikis, known as detachment-induced apoptosis, is a process of programmed cell death [76]. It can block metastasis by eliminating circulating cancer cells. However, in highly metastatic cancer cells, anoikis can be overcome and cancer cells can survive in a circulating condition until reaching a proper secondary site [77]. Anoikis is controlled by Bcl-2 family proteins. The pro-apoptotic proteins, such as Bax and the anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, interact during anoikis [78]. In addition, anti-apoptotic protein myeloid leukemia cell sequence-1 (MCL-1) and caveolin-1 (CAV-1) have also been demonstrated to suppress anoikis [79]. Anoikis has become potential therapeutic target, and discovering new natural products obtained from Chinese medicines targeting anoikis is of great interest [80].

The anti-metastatic study of arctigenin on colorectal cancer has been recently conducted. Arctigenin can induce anoikis via MAPKs signaling, inhibit EMT through increasing E-cadherin and decreasing N-cadherin, vimentin, β-catenin, and Snail, and downregulate MMP-2/9, so that inhibition on the tumor cell migration and invasion both in vitro and in vivo was achieved [81]. Imperatorin, an active furanocoumarin component obtained from the root of Angelica dahurica, has been demonstrated to sensitize anoikis by downregulating Mcl-1 protein and upregulating Bax in lung cancer [82]. As a major dietary flavonoid, quercetin was reported to induce apoptosis through the MAPKs pathway, regulate EMT markers including E-, N-cadherin, β-catenin, and snail and modulate MMPs and TIMPs in colorectal cancer [83]. Curcumin, a compound derived from the rhizome of turmeric, was reported to inhibit the migratory and invasive ability of lung cancer cells through sensitizing anoikis, which was associated with downregulation of Bcl-2 [84]. Such anoikis regulation was also observed in lung cancer cells challenged other single compounds obtained from Chinese medicine, such as artonin E [85], ecteinascidin 770 [86], renieramycin M [87], Oroxylin A [88], and so on. In addition, regulation on anoikis was also observed in tumor cells treated with various extracts from Chinese medicines. Annona muricata Linn from Annonaceae family has long been applied to treat different diseases. Recently, its leaf aqueous extract (B1 AMCE) has been reported to exhibit anti-metastatic property in breast cancer [89]. B1 AMCE can significantly suppress the metastasis of 4T1 breast cancer cells in vitro and in vivo via inducing their apoptosis. The aqueous extract of Andrographis paniculata was demonstrated to inhibit anoikis resistance in esophageal cancer [89]. The bibenzyl compounds from Dendrobium pulchellum[90] and the mixture of flavonoids extracted from Korean Citrus aurantium have been shown to induce apoptosis and inhibit metastasis of lung cancer cells [91].

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6. Regulation of miRNA-mediated gene expression

As negative regulators of gene expression, microRNAs (miRNAs) have been shown to modulate multiple biological functions, such as immune response, metabolism, and metastasis [92]. miRNAs mediate the expression of target protein through degrading its mRNA or inhibiting the translation of mRNA via binding to mRNA three prime untranslated region (3′UTR). There is a dual action of miRNAs in cancers, either functioning as cancer promoters or inhibitors. Nearly, all human tumors have the characteristic of miRNAs dysregulation [93]. Since miRNAs play an important role in the metastatic behaviors of cancer cells, developing natural products obtained from Chinese medicines targeting miRNAs may be a promising strategy to treat metastatic cancers.

Recently, the anti-metastatic property of arsenic trioxide (ATO) in chondrosarcoma has been elucidated. It was reported that ATO attenuate the metastasis of chondrosarcoma cells through inhibit miR-125b/Stat3 axis [94]. As a common antioxidant obtained from cruciferous plants, sulforaphane has been reported to inhibit the migratory and invasive ability of lung cancer both in vitro and in vivo. This action is mediated by miR-616-5p [95]. In addition, ginsenoside Rd (Rd), one of the chemical compounds in Panax Notoginseng Saponins, has been investigated for its anti-metastatic property recently. The results showed that Rd treatment inhibited the migratory and invasive ability of breast cancer both in vitro and in vivo via suppressing miR-18a-mediated Smad2 expression [96].

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7. Conclusion and future challenges

Accumulating evidence has demonstrated that Chinese medicine is an excellent source for the development of novel therapies for metastatic cancer. As mentioned above, the molecular mechanisms underlying the effects of potential anti-invasive and metastatic Chinese medicines include suppression of EMT (e.g., epithelial and mesenchymal markers), suppression of proteases expression (e.g., MMPs, uPA and Rho GTPases), suppression of cancer-induced angiogenesis (e.g., pro-angiogenic and anti-angiogenic factors), anoikis regulation of circulating tumor cells (e.g., pro-apoptotic and anti-apoptotic proteins), and regulation of miRNA-mediated gene expression (e.g., miR-125b, miR-616-5p and miR-18a). The chapter summarized the potential anti-invasive and metastatic drug candidates, which provided scientific evidence for clinically used Chinese medicines in the field of cancer therapy. Understanding of the underlying molecular mechanisms may in turn lead to discovery and development of novel anticancer drugs. Although these findings show the anti-metastatic potential of Chinese medicines, studies to evaluating the marked efficacies and determining the appropriate therapeutic doses of anti-metastatic Chinese medicines in animal models and clinical trials are still badly necessary in the future. In addition, the modern techniques such as nanoparticles which may improve the anti-cancer properties via better cellular uptake, enhanced bioavailability, and localization to targeted sites should also be studied in the future.

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Acknowledgments

The study was financially supported by grants from the research council of the University of Hong Kong (Project Codes: 104003422, 104004092, 104004460), the Research Grants Committee (RGC) of Hong Kong, HKSAR (Project Codes: 764708, 766211, 17152116), Wong’s Donation on Modern Oncology of Chinese Medicine (Project code: 200006276), Gala Family Trust (Project Code: 200007008), Government-Matching Grant Scheme (Project Code: 207060411) and Donation of Vita Green Health Products Co., Ltd. (Project cord: 200007477).

References

  1. 1. Siege RL, Miller KD and Jemal A. Cancer statistics. CA: A Cancer Journal for Clinicians. 2016;66:7-30. DOI: 10.3322/caac.21332
  2. 2. Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R and Jemal A. Cancer treatment and survivorship statistics. CA: A Cancer Journal for Clinicians. 2016;66:271-289. DOI: 10.3322/caac.21349
  3. 3. Weiss RA and McMichael AJ. Social and environmental risk factors in the emergence of infectious diseases. Nature Medicine. 2004;10:S70-S76. DOI: 10.1038/nm1150
  4. 4. Hanahan D and Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70. DOI: 10.1016/S0092-8674(00)81683-9
  5. 5. Hanahan D and Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144:646-674. DOI: 10.1016/j.cell.2011.02.013
  6. 6. Kumar S and Weaver VM. Mechanics, malignancy, and metastasis: The force journey of a tumor cell. Cancer and Metastasis Reviews. 2009;28:113-127. DOI: 10.1007/s10555-008-9173-4
  7. 7. Chambers AF, Groom AC and MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nature Reviews Cancer. 2002;2:563-572. DOI: 10.1038/nrc865
  8. 8. Sahai E. Mechanisms of cancer cell invasion. Current Opinion in Genetics & Development. 2005;15:87-96. DOI: 10.1016/j.gde.2004.12.002
  9. 9. Coghlin C and Murray GI. Current and emerging concepts in tumour metastasis. Journal of Pathology. 2010;222:1-15. DOI: 10.1002/path.2727
  10. 10. Brooks SA, Lomax-Browne HJ, Carter TM, Kinch CE and Hall DM. Molecular interactions in cancer cell metastasis. Acta Histochemica. 2010;112:3-25. DOI: 10.1016/j.acthis.2008.11.022
  11. 11. Helbig G, Christopherson KW, 2nd, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE and Nakshatri H. NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. Journal of Biological Chemistry. 2003;278:21631-21638. DOI: 10.1074/jbc.M300609200
  12. 12. Liotta LA. An attractive force in metastasis. Nature. 2001;410:24-25. DOI: 10.1038/35065180
  13. 13. Mohammad NH, ter Veer E, Ngai L, Mali R, van Oijen MG and van Laarhoven HW. Optimal first-line chemotherapeutic treatment in patients with locally advanced or metastatic esophagogastric carcinoma: Triplet versus doublet chemotherapy: A systematic literature review and meta-analysis. Cancer and Metastasis Reviews. 2015;34:429-441. DOI: 10.1007/s10555-015-9576-y
  14. 14. Liou SY, Stephens JM, Carpiuc KT, Feng W, Botteman MF and Hay JW. Economic burden of haematological adverse effects in cancer patients: A systematic review. Clinical Drug Investigation. 2007;27:381-396. DOI: 10.2165/00044011-200727060-00002
  15. 15. Park SI, Liao J, Berry JE, Li X, Koh AJ, Michalski ME, Eber MR, Soki FN, Sadler D, Sud S, Tisdelle S, Daignault SD, Nemeth JA, Snyder LA, Wronski TJ, Pienta KJ and McCauley LK. Cyclophosphamide creates a receptive microenvironment for prostate cancer skeletal metastasis. Cancer Research. 2012;72:2522-2532. DOI: 10.1158/0008-5472.CAN-11-2928
  16. 16. Daenen LG, Roodhart JM, van Amersfoort M, Dehnad M, Roessingh W, Ulfman LH, Derksen PW and Voest EE. Chemotherapy enhances metastasis formation via VEGFR-1-expressing endothelial cells. Cancer Research. 2011;71:6976-6985. DOI: 10.1158/0008-5472.CAN-11-0627
  17. 17. Feng Y, Wang N, Zhu M, Feng Y, Li H and Tsao S. Recent progress on anticancer candidates in patents of herbal medicinal products. Recent Patents on Food, Nutrition & Agriculture. 2011;3:30-48. DOI: 10.2174/2212798411103010030
  18. 18. Cragg GM and Newman DJ. Plants as a source of anti-cancer agents. Journal of Ethnopharmacology. 2005;100:72-79. DOI: 10.1016/j.jep.2005.05.011
  19. 19. Liu TG, Xiong SQ, Yan Y, Zhu H and Yi C. Use of chinese herb medicine in cancer patients: A survey in southwestern china. Evidence-based Complementary and Alternative Medicine. 2012;2012:769042. DOI: 10.1155/2012/769042
  20. 20. Yang G, Li X, Li X, Wang L, Li J, Song X, Chen J, Guo Y, Sun X, Wang S, Zhang Z, Zhou X and Liu J. Traditional chinese medicine in cancer care: A review of case series published in the chinese literature. Evidence-based Complementary and Alternative Medicine. 2012;2012:751046. DOI: 10.1155/2012/751046
  21. 21. Kalluri R and Weinberg RA. The basics of epithelial-mesenchymal transition. Journal of Clinical Investigation. 2009;119:1420-1428. DOI: 10.1172/JCI39104
  22. 22. Yang J and Weinberg RA. Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis. Developmental Cell. 2008;14:818-829. DOI: 10.1016/j.devcel.2008.05.009
  23. 23. Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, Baba H and Mori M. Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Science. 2010;101:293-299. DOI: 10.1111/j.1349-7006.2009.01419.x
  24. 24. Thiery JP, Acloque H, Huang RY and Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871-890. DOI: 10.1016/j.cell.2009.11.007
  25. 25. De Craene B and Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nature Reviews Cancer. 2013;13:97-110. DOI: 10.1038/nrc3447
  26. 26. Ko H. Geraniin inhibits TGF-beta1-induced epithelial-mesenchymal transition and suppresses A549 lung cancer migration, invasion and anoikis resistance. Bioorganic & Medicinal Chemistry Letters. 2015;25:3529-3534. DOI: 10.1016/j.bmcl.2015.06.093
  27. 27. Chaotham C, Pongrakhananon V, Sritularak B and Chanvorachote P. A Bibenzyl from Dendrobium ellipsophyllum inhibits epithelial-to-mesenchymal transition and sensitizes lung cancer cells to anoikis. Anticancer Research. 2014;34:1931-1938
  28. 28. Busaranon K, Plaimee P, Sritularak B and Chanvorachote P. Moscatilin inhibits epithelial-to-mesenchymal transition and sensitizes anoikis in human lung cancer H460 cells. Journal of Natural Medicines. 2016;70:18-27. DOI: 10.1007/s11418-015-0931-7
  29. 29. Unahabhokha T, Chanvorachote P and Pongrakhananon V. The attenuation of epithelial to mesenchymal transition and induction of anoikis by gigantol in human lung cancer H460 cells. Tumour Biology. 2016;37:8633-8641. DOI: 10.1007/s13277-015-4717-z
  30. 30. Huang SF, Horng CT, Hsieh YS, Hsieh YH, Chu SC and Chen PN. Epicatechin-3-gallate reverses TGF-beta1-induced epithelial-to-mesenchymal transition and inhibits cell invasion and protease activities in human lung cancer cells. Food and Chemical Toxicology. 2016;94:1-10. DOI: 10.1016/j.fct.2016.05.009
  31. 31. Li Q, Wang Y, Xiao H, Li Y, Kan X, Wang X, Zhang G, Wang Z, Yang Q, Chen X, Weng X, Chen Y, Zhou B, Guo Y, Liu X and Zhu X. Chamaejasmenin B, a novel candidate, inhibits breast tumor metastasis by rebalancing TGF-beta paradox. Oncotarget. 2016;7:48180-48192. DOI: 10.18632/oncotarget.10193
  32. 32. Venugopala KN, Govender R, Khedr MA, Venugopala R, Aldhubiab BE, Harsha S and Odhav B. Design, synthesis, and computational studies on dihydropyrimidine scaffolds as potential lipoxygenase inhibitors and cancer chemopreventive agents. Drug Design, Development and Therapy. 2015;9:911-921. DOI: 10.2147/DDDT.S73890
  33. 33. Shin VY, Jin HC, Ng EK, Sung JJ, Chu KM and Cho CH. Activation of 5-lipoxygenase is required for nicotine mediated epithelial-mesenchymal transition and tumor cell growth. Cancer Letters. 2010;292:237-245. DOI: 10.1016/j.canlet.2009.12.011
  34. 34. Homma J, Yamanaka R, Yajima N, Tsuchiya N, Genkai N, Sano M and Tanaka R. Increased expression of CCAAT/enhancer binding protein beta correlates with prognosis in glioma patients. Oncology Reports. 2006;15:595-601. DOI: 10.3892/or.15.3.595
  35. 35. Wang Q, Li H, Sun Z, Dong L, Gao L, Liu C and Wang X. Kukoamine A inhibits human glioblastoma cell growth and migration through apoptosis induction and epithelial-mesenchymal transition attenuation. Scientific Reports. 2016;6:36543. DOI: 10.1038/srep36543
  36. 36. Chang CC, Ling XH, Hsu HF, Wu JM, Wang CP, Yang JF, Fang LW and Houng JY. Siegesbeckia orientalis extract inhibits TGFbeta1-induced migration and invasion of endometrial cancer cells. Molecules. 2016;21. DOI: 10.3390/molecules21081021
  37. 37. Ko YS, Lee WS, Panchanathan R, Joo YN, Choi YH, Kim GS, Jung JM, Ryu CH, Shin SC and Kim HJ. Polyphenols from Artemisia annua L Inhibit Adhesion and EMT of Highly Metastatic Breast Cancer Cells MDA-MB-231. Phytotherapy Research. 2016;30:1180-1188. DOI: 10.1002/ptr.5626
  38. 38. Leeman MF, Curran S and Murray GI. New insights into the roles of matrix metalloproteinases in colorectal cancer development and progression. Journal of Pathology. 2003;201:528-534. DOI: 10.1002/path.1466
  39. 39. Lu S, Zhu Q, Zhang Y, Song W, Wilson MJ and Liu P. Dual-Functions of miR-373 and miR-520c by Differently Regulating the Activities of MMP2 and MMP9. Journal of Cellular Physiology. 2015;230:1862-1870. DOI: 10.1002/jcp.24914
  40. 40. Huang Q, Lan F, Wang X, Yu Y, Ouyang X, Zheng F, Han J, Lin Y, Xie Y, Xie F, Liu W, Yang X, Wang H, Dong L, Wang L and Tan J. IL-1beta-induced activation of p38 promotes metastasis in gastric adenocarcinoma via upregulation of AP-1/c-fos, MMP2 and MMP9. Molecular Cancer. 2014;13:18. DOI: 10.1186/1476-4598-13-18
  41. 41. Gomis-Ruth FX, Maskos K, Betz M, Bergner A, Huber R, Suzuki K, Yoshida N, Nagase H, Brew K, Bourenkov GP, Bartunik H and Bode W. Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature. 1997;389:77-81. DOI: 10.1038/37995
  42. 42. Raghu H, Sodadasu PK, Malla RR, Gondi CS, Estes N and Rao JS. Localization of uPAR and MMP-9 in lipid rafts is critical for migration, invasion and angiogenesis in human breast cancer cells. BMC Cancer. 2010;10:647. DOI: 10.1186/1471-2407-10-647
  43. 43. Gardel ML, Schneider IC, Aratyn-Schaus Y and Waterman CM. Mechanical integration of actin and adhesion dynamics in cell migration. Annual Review of Cell and Developmental Biology. 2010;26:315-333. DOI: 10.1146/annurev.cellbio.011209.122036
  44. 44. Vega FM and Ridley AJ. Rho GTPases in cancer cell biology. FEBS Letters. 2008;582:2093-2101. DOI: 10.1016/j.febslet.2008.04.039
  45. 45. Ridley AJ. Rho GTPases and cell migration. Journal of Cell Science. 2001;114:2713-2722
  46. 46. Maxwell T, Chun SY, Lee KS, Kim S and Nam KS. The anti-metastatic effects of the phytoestrogen arctigenin on human breast cancer cell lines regardless of the status of ER expression. International Journal of Oncology. 2017;50:727-735. DOI: 10.3892/ijo.2016.3825
  47. 47. Jiang K, Lu Q, Li Q, Ji Y, Chen W and Xue X. Astragaloside IV inhibits breast cancer cell invasion by suppressing Vav3 mediated Rac1/MAPK signaling. International Immunopharmacology. 2017;42:195-202. DOI: 10.1016/j.intimp.2016.10.001
  48. 48. Lee CY, Hsieh SL, Hsieh S, Tsai CC, Hsieh LC, Kuo YH and Wu CC. Inhibition of human colorectal cancer metastasis by notoginsenoside R1, an important compound from Panax notoginseng. Oncology Reports. 2017;37:399-407. DOI: 10.3892/or.2016.5222
  49. 49. Lin CL, Hsieh SL, Leung W, Jeng JH, Huang GC, Lee CT and Wu CC. 2,3,5,4′-tetrahydroxystilbene-2-O-beta-D-glucoside suppresses human colorectal cancer cell metastasis through inhibiting NF-kappaB activation. International Journal of Oncology. 2016;49:629-638. DOI: 10.3892/ijo.2016.3574
  50. 50. Huang H, Du T, Xu G, Lai Y, Fan X, Chen X, Li W, Yue F, Li Q, Liu L and Li K. Matrine suppresses invasion of castration-resistant prostate cancer cells by downregulating MMP-2/9 via NF-kappaB signaling pathway. International Journal of Oncology. 2017;50:640-648. DOI: 10.3892/ijo.2016.3805
  51. 51. Lin CC, Chen CC, Kuo YH, Kuo JT, Senthil Kumar KJ and Wang SY. 2,3,5-Trimethoxy-4-cresol, an anti-metastatic constituent from the solid-state cultured mycelium of Antrodia cinnamomea and its mechanism. Journal of Natural Medicines. 2015;69:513-521. DOI: 10.1007/s11418-015-0916-6
  52. 52. Farha AK, Dhanya SR, Mangalam SN and Remani P. Anti-metastatic effect of deoxyelephantopin from Elephantopus scaber in A549 lung cancer cells in vitro. Natural Product Research. 2015;29:2341-2345. DOI: 10.1080/14786419.2015.1012165
  53. 53. Wu SH, Hsiao YT, Kuo CL, Yu FS, Hsu SC, Wu PP, Chen JC, Hsia TC, Liu HC, Hsu WH and Chung JG. Bufalin inhibits NCI-H460 human lung cancer cell metastasis in vitro by inhibiting MAPKs, MMPs, and NF-kappaB pathways. American Journal of Chinese Medicine. 2015;43:1247-1264. DOI: 10.1142/S0192415X15500718
  54. 54. Wang N, Zhu M, Tsao SW, Man K, Zhang Z and Feng Y. Up-regulation of TIMP-1 by genipin inhibits MMP-2 activities and suppresses the metastatic potential of human hepatocellular carcinoma. PLoS One. 2012;7:e46318. DOI: 10.1371/journal.pone.0046318
  55. 55. Wang N, Tan HY, Li L, Yuen MF and Feng Y. Berberine and Coptidis Rhizoma as potential anticancer agents: Recent updates and future perspectives. Journal of Ethnopharmacology. 2015;176:35-48. DOI: 10.1016/j.jep.2015.10.028
  56. 56. Tsang CM, Lau EP, Di K, Cheung PY, Hau PM, Ching YP, Wong YC, Cheung AL, Wan TS, Tong Y, Tsao SW and Feng Y. Berberine inhibits Rho GTPases and cell migration at low doses but induces G2 arrest and apoptosis at high doses in human cancer cells. International Journal of Molecular Medicine. 2009;24:131-138. DOI: 10.3892/ijmm_00000216
  57. 57. Becker MS, Muller PM, Bajorat J, Schroeder A, Giaisi M, Amin E, Ahmadian MR, Rocks O, Kohler R, Krammer PH and Li-Weber M. The anticancer phytochemical rocaglamide inhibits Rho GTPase activity and cancer cell migration. Oncotarget. 2016;7:51908-51921. DOI: 10.18632/oncotarget.10188
  58. 58. Chang PY, Hsieh MJ, Hsieh YS, Chen PN, Yang JS, Lo FC, Yang SF and Lu KH. Tricetin inhibits human osteosarcoma cells metastasis by transcriptionally repressing MMP-9 via p38 and Akt pathways. Environmental Toxicology. 2016;Nov 8. DOI: 10.1002/tox.22380
  59. 59. Cheng HL, Hsieh MJ, Yang JS, Lin CW, Lue KH, Lu KH and Yang SF. Nobiletin inhibits human osteosarcoma cells metastasis by blocking ERK and JNK-mediated MMPs expression. Oncotarget. 2016;7:35208-35223. DOI: 10.18632/oncotarget.9106
  60. 60. Lin CM, Lin YL, Ho SY, Chen PR, Tsai YH, Chung CH, Hwang CH, Tsai NM, Tzou SC, Ke CY, Chang J, Chan YL, Wang YS, Chi KH and Liao KW. The inhibitory effect of 7, 7”-dimethoxyagastisflavone on the metastasis of melanoma cells via the suppression of F-actin polymerization. Oncotarget. 2016;Jul 30. DOI: 10.18632/oncotarget.10960
  61. 61. Shin SY, Kim CG, Jung YJ, Jung Y, Jung H, Im J, Lim Y and Lee YH. Euphorbia humifusa Willd exerts inhibition of breast cancer cell invasion and metastasis through inhibition of TNFalpha-induced MMP-9 expression. BMC Complementary and Alternative Medicine. 2016;16:413. DOI: 10.1186/s12906-016-1404-6
  62. 62. Chung TW, Choi H, Lee JM, Ha SH, Kwak CH, Abekura F, Park JY, Chang YC, Ha KT, Cho SH, Chang HW, Lee YC and Kim CH. Oldenlandia diffusa suppresses metastatic potential through inhibiting matrix metalloproteinase-9 and intercellular adhesion molecule-1 expression via p38 and ERK1/2 MAPK pathways and induces apoptosis in human breast cancer MCF-7 cells. Journal of Ethnopharmacology. 2017;195:309-317. DOI: 10.1016/j.jep.2016.11.036
  63. 63. Carmeliet P and Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249-257. DOI: 10.1038/35025220
  64. 64. Tonini T, Rossi F and Claudio PP. Molecular basis of angiogenesis and cancer. Oncogene. 2003;22:6549-6556. DOI: 10.1038/sj.onc.1206816
  65. 65. Eichhorn ME, Kleespies A, Angele MK, Jauch KW and Bruns CJ. Angiogenesis in cancer: Molecular mechanisms, clinical impact. Langenbeck's Archives of Surgery. 2007;392:371-379. DOI: 10.1007/s00423-007-0150-0
  66. 66. Baeriswyl V and Christofori G. The angiogenic switch in carcinogenesis. Seminars in Cancer Biology. 2009;19:329-337. DOI: 10.1016/j.semcancer.2009.05.003
  67. 67. Wang X, Wang N, Li H, Liu M, Cao F, Yu X, Zhang J, Tan Y, Xiang L and Feng Y. Up-regulation of PAI-1 and down-regulation of uPA are involved in suppression of invasiveness and motility of hepatocellular carcinoma cells by a natural compound berberine. International Journal of Molecular Sciences. 2016;17:577. DOI: 10.3390/ijms17040577
  68. 68. Tsang CM, Cheung KC, Cheung YC, Man K, Lui VW, Tsao SW and Feng Y. Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma. Biochimica et Biophysica Acta. 2015;1852:541-551. DOI: 10.1016/j.bbadis.2014.12.004
  69. 69. Sinha S, Khan S, Shukla S, Lakra AD, Kumar S, Das G, Maurya R and Meeran SM. Cucurbitacin B inhibits breast cancer metastasis and angiogenesis through VEGF-mediated suppression of FAK/MMP-9 signaling axis. International Journal of Biochemistry & Cell Biology. 2016;77:41-56. DOI: 10.1016/j.biocel.2016.05.014
  70. 70. Zhang L, Qian H, Sha M, Luan Z, Lin M, Yuan D, Li X, Huang J and Ye L. Downregulation of HOTAIR expression mediated anti-metastatic effect of artesunate on cervical cancer by inhibiting COX-2 expression. PLoS One. 2016;11:e0164838. DOI: 10.1371/journal.pone.0164838
  71. 71. Wang N, Feng Y, Lau EP, Tsang C, Ching Y, Man K, Tong Y, Nagamatsu T, Su W and Tsao S. F-actin reorganization and inactivation of rho signaling pathway involved in the inhibitory effect of Coptidis Rhizoma on hepatoma cell migration. Integrative Cancer Therapies. 2010;9:354-364. DOI: 10.1177/1534735410379121
  72. 72. Tan HY, Wang N, Tsao SW, Zhang Z and Feng Y. Suppression of vascular endothelial growth factor via inactivation of eukaryotic elongation factor 2 by alkaloids in Coptidis rhizome in hepatocellular carcinoma. Integrative Cancer Therapies. 2014;13:425-434. DOI: 10.1177/1534735413513635
  73. 73. Im M, Kim A and Ma JY. Ethanol extract of baked Gardeniae Fructus exhibits in vitro and in vivo anti-metastatic and anti-angiogenic activities in malignant cancer cells: Role of suppression of the NF-kappaB and HIF-1alpha pathways. International Journal of Oncology. 2016;49:2377-2386. DOI: 10.3892/ijo.2016.3742
  74. 74. Kim A, Im M, Gu MJ and Ma JY. Ethanol extract of Lophatheri Herba exhibits anti-cancer activity in human cancer cells by suppression of metastatic and angiogenic potential. Scientific Reports. 2016;6:36277. DOI: 10.1038/srep36277
  75. 75. Wang N, Feng Y, Cheung F, Wang X, Zhang Z and Feng Y. A Chinese medicine formula Gegen Qinlian decoction suppresses expansion of human renal carcinoma with inhibition of matrix metalloproteinase-2. Integrative Cancer Therapies. 2015;14:75-85. DOI: 10.1177/1534735414550036
  76. 76. Chiarugi P and Giannoni E. Anoikis: A necessary death program for anchorage-dependent cells. Biochemical Pharmacology. 2008;76:1352-1364. DOI: 10.1016/j.bcp.2008.07.023
  77. 77. Guadamillas MC, Cerezo A and Del Pozo MA. Overcoming anoikis--pathways to anchorage-independent growth in cancer. Journal of Cell Science. 2011;124:3189-3197. DOI: 10.1242/jcs.072165
  78. 78. Fulda S and Debatin KM. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006;25:4798-4811. DOI: 10.1038/sj.onc.1209608
  79. 79. Chunhacha P, Pongrakhananon V, Rojanasakul Y and Chanvorachote P. Caveolin-1 regulates Mcl-1 stability and anoikis in lung carcinoma cells. American Journal of Physiology. Cell Physiology. 2012;302:C1284-C1292. DOI: 10.1152/ajpcell.00318.2011
  80. 80. Wang N and Feng Y. Elaborating the role of natural products-induced autophagy in cancer treatment: Achievements and artifacts in the state of the art. BioMed Research International. 2015;2015:934207. DOI: 10.1155/2015/934207
  81. 81. Han YH, Kee JY, Kim DS, Mun JG, Jeong MY, Park SH, Choi BM, Park SJ, Kim HJ, Um JY and Hong SH. Arctigenin inhibits lung metastasis of colorectal cancer by regulating cell viability and metastatic phenotypes. Molecules. 2016;21. DOI: 10.3390/molecules21091135
  82. 82. Choochuay K, Chunhacha P, Pongrakhananon V, Luechapudiporn R and Chanvorachote P. Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells. Journal of Natural Medicines. 2013;67:599-606. DOI: 10.1007/s11418-012-0719-y
  83. 83. Kee JY, Han YH, Kim DS, Mun JG, Park J, Jeong MY, Um JY and Hong SH. Inhibitory effect of quercetin on colorectal lung metastasis through inducing apoptosis, and suppression of metastatic ability. Phytomedicine. 2016;23:1680-1690. DOI: 10.1016/j.phymed.2016.09.011
  84. 84. Pongrakhananon V, Nimmannit U, Luanpitpong S, Rojanasakul Y and Chanvorachote P. Curcumin sensitizes non-small cell lung cancer cell anoikis through reactive oxygen species-mediated Bcl-2 downregulation. Apoptosis. 2010;15:574-585. DOI: 10.1007/s10495-010-0461-4
  85. 85. Wongpankam E, Chunhacha P, Pongrakhananon V, Sritularak B and Chanvorachote P. Artonin E mediates MCL1 down-regulation and sensitizes lung cancer cells to anoikis. Anticancer Research. 2012;32:5343-5351
  86. 86. Powan P, Saito N, Suwanborirux K and Chanvorachote P. Ecteinascidin 770, a tetrahydroisoquinoline alkaloid, sensitizes human lung cancer cells to anoikis. Anticancer Research. 2013;33:505-512
  87. 87. Sirimangkalakitti N, Chamni S, Suwanborirux K and Chanvorachote P. Renieramycin M sensitizes anoikis-resistant H460 lung cancer cells to anoikis. Anticancer Research. 2016;36:1665-1671
  88. 88. Wei L, Dai Q, Zhou Y, Zou M, Li Z, Lu N and Guo Q. Oroxylin A sensitizes non-small cell lung cancer cells to anoikis via glucose-deprivation-like mechanisms: c-Src and hexokinase II. Biochimica et Biophysica Acta. 2013;1830:3835-3845. DOI: 10.1016/j.bbagen.2013.03.009
  89. 89. Syed Najmuddin SU, Romli MF, Hamid M, Alitheen NB and Nik Abd Rahman NM. Anti-cancer effect of Annona Muricata Linn Leaves Crude Extract (AMCE) on breast cancer cell line. BMC Complement Altern Med. 2016;16:311. DOI: 10.1186/s12906-016-1290-y
  90. 90. Chanvorachote P, Kowitdamrong A, Ruanghirun T, Sritularak B, Mungmee C and Likhitwitayawuid K. Anti-metastatic activities of bibenzyls from Dendrobium pulchellum. Natural Products Communications. 2013;8:115-118
  91. 91. Park KI, Park HS, Kim MK, Hong GE, Nagappan A, Lee HJ, Yumnam S, Lee WS, Won CK, Shin SC and Kim GS. Flavonoids identified from Korean Citrus aurantium L. inhibit non-small cell lung Cancer growth in vivo and in vitro. Journal of Functional Foods. 2014;7:287-297. DOI: 10.1016/j.jff.2014.01.032
  92. 92. Chen PS, Su JL and Hung MC. Dysregulation of microRNAs in cancer. Journal of Biomedical Science. 2012;19:90. DOI: 10.1186/1423-0127-19-90
  93. 93. Tili E, Michaille JJ and Croce CM. MicroRNAs play a central role in molecular dysfunctions linking inflammation with cancer. Immunology Reviews. 2013;253:167-184. DOI: 10.1111/imr.12050
  94. 94. Bao X, Ren T, Huang Y, Wang S, Zhang F, Liu K, Zheng B and Guo W. Induction of the mesenchymal to epithelial transition by demethylation-activated microRNA-125b is involved in the anti-migration/invasion effects of arsenic trioxide on human chondrosarcoma. Journal of Experimental & Clinical Cancer Research. 2016;35:129. DOI: 10.1186/s13046-016-0407-y
  95. 95. Wang DX, Zou YJ, Zhuang XB, Chen SX, Lin Y, Li WL, Lin JJ and Lin ZQ. Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3beta/beta-catenin signaling pathways. Acta Pharmacologica Sinica. 2017;38:241-251. DOI: 10.1038/aps.2016.122
  96. 96. Wang P, Du X, Xiong M, Cui J, Yang Q, Wang W, Chen Y and Zhang T. Ginsenoside Rd attenuates breast cancer metastasis implicating derepressing microRNA-18a-regulated Smad2 expression. Scientific Reports. 2016;6:33709. DOI: 10.1038/srep33709

Written By

Wei Guo, Ning Wang and Yibin Feng

Submitted: November 14th, 2016 Reviewed: April 5th, 2017 Published: July 12th, 2017