ADAMTS proteases consist of 19 secreted metalloproteinases that have been implicated in oncogenic and tumor-protective functions (1–3). In recent years, there has been an increase in the number of known substrates of ADAMTS family members secreted by cancer and stromal cells (4–12). A variety of biological functions such as cell proliferation, migration, invasion, and angiogenesis have been attributed to the interaction of these enzymes with regulatory factors or to the cleavage of extracellular matrix components through their protein hydrolase activity (7, 13–18).

Initially, the link between ADAMTS18 and cancer was based on the altered mode of action of ADAMTS18 in different types of cancer (19–21). However, new evidence suggests that the complexity of ADAMTS18’s mode of action in cancer has extended to fine-tuned factors in cell signaling pathways and tumor microenvironment. Here, we will focus on the latest research advances to systematically introduce the biological functions and mechanisms of ADAMTS18 in tumorigenesis and development, as well as its close connection with tumor diagnosis and prognosis. It is hypothesized that fibronectin, as a candidate substrate and interacting protein, may be involved in the regulation of the tumor microenvironment by ADAMTS18 (22, 23). To date, there is a gap in clinical targeted drug studies for ADAMTS18, and we will provide examples of ADAMTS18 in combination with cisplatin and curcumin to provide new references for tumor therapy (24–28).

ADAMTS proteases share a multi-domain organization that includes a signal peptide, a prodomain, a metalloproteinase domain, a disintegrin-like domain, a thrombospondin type1 motif (TSR), a Cys-rich domain, and a spacer region (1, 29). It has been reported that the ancillary domains of some ADAMTS proteases mediate substrate recognition (30–33), but it is not clear whether ADAMTS18 is consistent with this phenomenon. As illustrated in Figure 1 , the ancillary domain of ADAMTS18 is composed of the first TSR, Cys-rich domain, spacer region, five additional C-terminal TSR repeats, and protease and lacunin (PLAC) motif (34). All ADAMTS proteases have a furin cleavage site which releases mature proteins by cleaving prodomain, and ADAMTS18 is no exception (35). In addition, there is a thrombin cleavage site between Arg775 and Ser776 in the spacer region of ADAMTS18, which releases the C-terminal 45-kDa platelet active fragment composed of five TSR repeats and PLAC motif after being cleaved by thrombin (35, 36). Biochemical and 3-dimensional structural data showed that the members of the ADAMTS family have a catalytic mechanism similar to that of MMP and ADAM, involving three conservative His residues and zinc atoms (37, 38). In addition, a unique property of ADAMTS proteases is found in the crystal structures of the catalytic domain of ADAMTS4 and 5, which can balance the open structure that binds Ca²⁺ and the closed structure that releases Ca²⁺ (2). In these two conformations, ADAMTS proteases may regulate their catalytic actions via binding accessory proteins and substrates (2).

Data from Gene Expression Profiling Interactive Analysis (GEPIA) suggest that ADAMTS18 is associated with cancer because of their altered expression in different tumors. ADAMTS18 is located at 16q23.1 in the human genome, and heterozygous deletions in the 16q23 region have been strongly associated with a variety of cancers (19, 39, 40). Increasing evidence suggests that hypermethylation of the ADAMTS18 promoter CpG Islands (CGI) leads to epigenetic inactivation in a variety of cancers, thus making ADAMTS18 a tumor suppressor gene (TSG) (19, 41). ADAMTS18 has been reported to have tumor suppressor activity in esophageal adenocarcinoma, nasopharyngeal carcinoma, colorectal carcinoma, breast carcinoma, lung carcinoma, cervical carcinoma, and clear cell renal cell carcinoma (19, 28, 42–45). Furthermore, the methylation frequency of ADAMTS18 varies in a variety of tumor tissues (40, 43). For example, the methylation frequencies of ADAMTS18 in breast, colorectal, and pancreatic cancers are 70.8%, 49%, and 39%, respectively, which may explain the mechanism of action of ADAMTS18 in different types of cancers (40, 43). In addition to promoter methylation, the gene mutation is another way to inactivate ADAMTS18. A comprehensive mutation study identified two missense mutations (R382K and K455T, both located in the catalytic region of metalloproteinases) in ADAMTS18 in colon cancer (46, 47). Moreover, in human melanoma, 19 members belonging to the ADAMTS family were sequenced, with ADAMTS18 having the highest mutation frequency (20). Notably, ADAMTS18 was found to be upregulated in gastric adenocarcinoma and pancreas adenocarcinoma tissues, suggesting that ADAMTS18 also has oncogenic activity (21, 48).

Cancer recurrence and metastasis is a major problem for cancer patients. Therefore, it is significant to explore independent prognostic indicators for cancer intervention and treatment. In the large number of primary cancer samples, ADAMTS18 downregulation was found to be the result of promoter methylation, and gene methylation is an ideal biomarker for early diagnosis or efficacy monitoring (19, 49–52). Since these changes occur in the early stages of cancer, it has been hypothesized that ADAMTS18 can aid in early cancer diagnosis and prognosis. For example, high expression of ADAMTS18 in lung cancer is positively correlated with high overall survival (OS) in -stage patients (28). In addition, low expression of ADAMTS18 in cervical cancer is positively associated with high tumor stage, positive lymph node metastasis, distant metastasis, short OS, and disease-free survival (DFS) (44). In gastric adenocarcinoma, ADAMTS18 is positively correlated with tumor differentiation, lymph node metastasis, TNM stage, short OS (21, 53). The immune positivity of ADAMTS18 was also found to be higher in metastatic lymph nodes than in non-metastatic lymph tissue in pancreas adenocarcinoma (48). In addition, ADAMTS18 in invasive ductal carcinoma (IDC) of the breast is correlated not only with tumor histological grade but also with estrogen receptor (ER), progesterone receptor (PR), and Ki67, which are markers of breast cancer (54). If ER and PR are positive in tumor tissues, their proliferation is hormone-dependent, and high expression of ER and PR is associated with a better prognosis (55). According to a hypoxia risk model which has been proposed for the diagnosis and prognosis of ESCC, we can predict 1-, 3-, and 5-year survival of patients, and ADAMTS18 is one of the key hypoxia-related genes (HRGs) of this model (56). In conclusion, ADAMTS18 may be a good prognostic factor for many cancer types ( Table 1 ).

ADAMTS18 has been widely documented to play a role as a TSG in most types of cancer. In this context, the large number of tumor cells and mouse tumor models have been established and analyzed for the function of ADAMTS18, including cell proliferation signals, cell death patterns, cell migration, and invasion. In the AOM/DSS-induced colitis-associated colon cancer (CAC) mouse model, ADAMTS18 gene deletion promotes cancer cell proliferation and inhibits cancer cell apoptosis (42). An ADAMTS18 mutant melanoma cell line was established by simulating standard conditions in vivo (20). In addition, mutant melanoma cells reduce their dependence on factors required for cell growth, suggesting a growth-promoting effect of mutant ADAMTS18 on melanoma (20). Mutant ADAMTS18 also promotes migration and invasion of melanoma cells in vitro by reducing adhesion to laminin-I (20). This was further confirmed by histopathological results of subcutaneous injection tests in nude mice (20). In the sunitinib-resistant clear cell renal cell carcinoma (ccRCC) cell model, ADAMTS18 was shown to down-regulate the expression levels of NCOA4, FTH1, and p53, and induced ferritin deposition to inhibit proliferation (26). In most cases, the tumor suppressor protein p53 (TP53) inhibits iron oxidation through multiple pathways (58). NCOA4 and FTH1 mediate ferritin phagocytosis, and decreased levels of their expression increase ferritin levels and induce ferroptosis (59, 60). In addition, similar results were observed in axitinib-resistant cells and animal models, where ADAMTS18 inhibited the development of ccRCC (27). In renal clear cell carcinoma, there is positive feedback regulation between ADAMTS18 and miR-148 (25). Therefore, ADAMTS18 could play a tumor-suppressive role in renal clear cell carcinoma by inhibiting autophagy (61). These are summarized in Table 1 .

In recent decades, previous studies have made breakthroughs in the tumor suppressor activity and mechanisms of ADAMTS18. Multiple intracellular signaling pathways, such as NF-κB, AKT, EMT, Wnt/β-catenin, p38 MAPK/ERK1/2, and epidermal growth factor receptor (EGFR) assist ADAMTS18 to play important roles in different types of tumors (28, 42, 43). In vivo and in vitro experiments have shown that ADAMTS18 inhibits migration and invasion of breast cancer cells (43). In this process, breast cancer cells were found to exhibit an epithelial phenotype, with higher expression of the epithelial marker E-cadherin and down-regulated expression of the mesenchymal marker Snail (43). The AKT kinase and NF-κB signaling pathways make it one of the most common pathways in cancer. In addition, AKT-dependent activation of the NF-κB signaling pathway has been shown to induce EMT (62). Following previous studies, ADAMTS18 showed tumor suppressive effects by inhibiting epithelial-mesenchymal transition through inhibiting the NF-κB/AKT signaling pathway in breast cancer (43). In the HER2 transgenic spontaneous mammary tumor mouse model, we found a similar conclusion that ADAMTS18 deletion leads to the enhancement of integrin-mediated PI3K/AKT, ERK, and JNK signal activity, which increases the risk of mammary hyperplasia and breast cancer occurrence and metastasis (57). In the AOM/DSS-induced CAC mouse model, the number of β-catenin, cyclin D1, and c-myc positive cells is increased in ADAMTS18 KO mice compared to WT littermates, whereas the expression of E-cadherin is decreased (42). The Wnt/β-catenin signaling pathway plays an important role in the development, progression, metastasis, and invasion of CRC (63). When the amount of β-catenin in the cytoplasm steadily accumulates, β-catenin is transferred from the cytoplasm to the nucleus and binds to transcription factors, initiating the transcription of downstream target genes cyclin D1 and c-myc (64). E-cadherin is known to be an epithelial marker, downregulation of E-cadherin causes epithelial cells to lose polarity and adhesion, promoting tumor migration and invasion (65, 66). In addition, in CAC, E-cadherin binds to β-catenin to form a complex that binds to the cytoskeleton and prevents β-catenin from translocating to the nucleus, thus preventing the activation of the Wnt/β-catenin signaling pathway (67). Histological results from the CAC model showed that ADAMTS18 deletion up-regulates phosphorylated p38 MAPK and ERK1/2 expression (42). The tumor-suppressive mechanism of some ADAMTS family members, such as ADAMTS8 and ADAMTS12, is manifested by antagonizing ERK signaling (68, 69), and the ERK/P38 MAPK signaling pathway inhibits tumor growth in colon adenocarcinoma (70). In addition, the function of ERK/P38 MAPK in regulating cell proliferation and apoptosis has been reported (71). Down-regulation of ADAMTS18 promotes apoptosis and promotes colorectal cancer cell proliferation, which is consistent with the above phenomenon (42). Taken together, the down-regulation of ADAMTS18 promotes colon cancer development and progression by promoting Wnt/β-catenin and p38 MAPK/ERK1/2 signaling pathways (42). Furthermore, the mechanism by which ADAMTS18 increases the sensitivity of lung cancer cells to cisplatin is that ADAMTS18 acts as an inhibitor of epidermal growth factor receptor/protein kinase B (EGFR/AKT) signaling antagonist (28). In conclusion, understanding the molecular mechanism of ADAMTS18 as a TSG will help to develop new therapies targeting tumorigenesis and metastasis. These are also described in Figure 2 .

The tumor microenvironment places cancer cells within a network of stromal cells that are comprised of fibroblasts vascular cells and inflammatory immune cells (29, 72, 73). In addition, extracellular matrix (ECM) and cytokines/growth factors are representative components of TME (29). TME regulates tumor proliferation and invasion, angiogenesis, inflammation, immune escape, and drug resistance through the modulation of this complex system (74). ADAMTS is an enzyme that degrades stroma. Tumor cells degrade stroma by secreting ADAMTS, which in turn promotes tumor cell invasion and metastasis. In addition, inflammatory cells and fibroblasts in the tumor microenvironment can also secrete ADAMTS, which plays an important role in promoting tumor development. Secreted or membrane-associated metalloprotease activities have been traditionally associated with an increase in the tumorigenic potential of tumor cells (75). These ADAMTS can modify the primary tumor microenvironment by proteolytic-dependent or independent mechanisms. About ADAMTS18, research in this area is still vague. Thus, only four aspects of inflammation, immunity, microvessel formation, and extracellular matrix are described next.

Since ADAMTS18 has the potential to be a prognostic indicator for a variety of cancers, it is of great significance to study ADAMTS18 as an anticancer-targeted drug. So far, there is a gap in this research although ADAMTS18 in combination with some drugs has shown therapeutic effects in the field of anti-cancer (24–28). ADAMTS18 not only reverses the resistance of ccRCC to sunitinib and axitinib in combination with curcumin but also independently increases the sensitivity of lung cancer cells to cisplatin (26–28). Cisplatin is a widely used anticancer drug in the clinic, but its resistance reduces its clinical value (109, 110). Previous data showed that ADAMTS18 increases the sensitivity of lung cancer cells to cisplatin, thereby improving patient survival to some extent (28). As mentioned earlier, ADAMTS18 was found to inhibit the proliferation, migration, and invasion of lung cancer cells and to block lung cancer cells in the G0/G1 phase, suggesting that ADAMTS18 itself has a tumor-suppressing effect (28). ADAMTS18 has also been illustrated to increase lung cancer cell sensitivity to cisplatin by suppressing the EGFR/AKT signaling pathway (28). In addition, a new study revealed that the expression level of ADAMTS18 in HER2-positive breast tumor samples at the initial stage of post trastuzumab treatment is higher than that in recurrent HER2-positive tumor samples after post trastuzumab treatment, suggesting that ADAMTS18 can be responsible for a reference factor for drug resistance therapy (57).

Curcumin, as a medicinal plant, has become a hotspot of tumor research in recent years due to its excellent anti-inflammatory and antioxidant effects (111, 112). ADAMTS18 can assist curcumin in inhibiting the occurrence and development of ccRCC. Curcumin down-regulates the NF-κB and AKT signaling pathways, reverses the methylation of ADAMTS18 in ccRCC, and inhibits the growth of cancer cells by up-regulating ADAMTS18 expression (24). In addition, curcumin inhibits autophagy in cancer cells and achieves its tumor-suppressive effect by modulating the positive feedback mechanism between miR-148 and ADAMTS18 (25). Sunitinib and axitinib, as tyrosine kinase inhibitors with strong anti-tumor cell proliferation and anti-angiogenic effects, have been considered targeted drugs for the treatment of ccRCC, but their drug resistance is still an urgent clinical problem (113, 114). Curcumin was found to increase the sensitivity of sunitinib to ccRCC cells, and this mechanism is realized through the induction of ferroptosis by ADAMTS18 in ccRCC cells (26). The Chinese herbal compound SanHuang decoction containing curcumin can reverse the drug resistance of axitinib in ccRCC cells by up-regulating the expression of ADAMTS18 (27). In addition, the Chinese herbal compound SanHuang decoction and ADAMTS18 have a synergistic effect by increasing the proportion of CD8+ and CD4+T cells and reducing the ratio of CD45+/PD-L1 to increase tumor immune infiltration and inhibiting immune escape (27, 115).

ADAMTS18 fulfills multiple distinct roles in tumor tissues, affecting intracellular signals and tumor microenvironment, which is reflected in the complexity of biological functions and different expression patterns of ADAMTS18 in different types of tumor tissues (19, 20). From an oncological point of view, the relationship between the tumor-promoting and anti-tumorigenic properties of ADAMTS18 and specific substrates and interacting proteins has not been well explained, although the biological functions of ADAMTS18 have been extensively reported in the literature. In addition, the information provided by the established ADAMTS18 cell and mouse models is still unconvincing without the support of extensive clinical data. Therefore, more studies on the molecular mechanisms by which ADAMTS18 regulates cancer are needed in the future, which will not only contribute to the understanding of the physiological mechanisms of ADAMTS family members but also to the development of less toxic cancer therapies.

WG: Writing – original draft. YZ: Conceptualization, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review & editing.