Next Article in Journal
A Comparative Study on the Paradoxical Relationship Between Heavy Metal Exposure and Kidney Function
Previous Article in Journal
Epilepsy Diagnosis from EEG Signals Using Continuous Wavelet Transform-Based Depthwise Convolutional Neural Network Model
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Diagnostics
Volume 15
Issue 1
10.3390/diagnostics15010085
diagnostics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

DKK1 and Its Receptors in Esophageal Adenocarcinoma: A Promising Molecular Target

by
Markos Despotidis
1,*,
Orestis Lyros
2,
Tatiana S. Driva
3,
Panagiotis Sarantis
4,
Emmanouil I. Kapetanakis
5,*,
Adam Mylonakis
1,
Andreas Mamilos
6,7,
Stratigoula Sakellariou
3 and
Dimitrios Schizas
1
1
First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece
2
Fourth Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece
3
First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
4
Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
5
Department of Thoracic Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece
6
Institute of Pathology, University of Regensburg, 93053 Bavaria, Germany
7
Department of Pathology, German Oncology Center, Limassol 4108, Cyprus
*
Authors to whom correspondence should be addressed.
Diagnostics 2025, 15(1), 85; https://doi.org/10.3390/diagnostics15010085
Submission received: 7 November 2024 / Revised: 26 December 2024 / Accepted: 1 January 2025 / Published: 2 January 2025
(This article belongs to the Section Pathology and Molecular Diagnostics)
Browse Figures
Versions Notes

Abstract

Esophageal adenocarcinoma (EAC) is an aggressive gastrointestinal (GI) malignancy with increasing incidence. Despite the recent progress in targeted therapies and surgical approaches, the survival rates of esophageal adenocarcinoma patients remain poor. The Dickkopf (DKK) proteins are secretory proteins known mainly as antagonists of the Wnt/β-catenin signaling pathway, which is considered an oncogene. However, it has been shown that in several GI cancers, including esophageal cancer, DKK1 may act as an oncogene itself through Wnt-independent signaling pathways. LRP5\6 and Kremen1/2 (Krm1/2) are transmembrane receptors to which the DKK proteins are mainly known to bind. CKAP4 (cytoskeleton-associated protein 4) is a novel receptor of DKK1, and the DKK1-CKAP4 pathway seems to be crucial in the role of DKK1 as an oncogene. The aim of this review is to feature the essential role of DKK1 and its receptors in carcinogenesis with a focus on EAC in an era of urgent need for specific biomarkers along with improved targeted therapies.

1. Introduction

Esophageal cancer (EAC), being the eighth most common cancer and the sixth most common cause of cancer-related death worldwide [1], is characterized by poor prognosis and often delayed diagnosis in the western world; gastroesophageal junction (GEJ) adenocarcinoma incidence kept increasing during the last decades [2]. Despite recent progress in oncological management, including multimodality treatment, targeted therapies as well as modern surgical procedures, the survival rate of esophageal cancer patients remains low [3]. Recent advances in oncological therapies for solid tumors dictate a more biomarker-mediated approach rather than a histology-driven approach. In the case of esophageal adenocarcinoma, there are still no biomarkers in the clinical setting. Thus, for patients with esophageal cancer, we are still in urgent need of discovering potential biomarkers with therapeutic relevance. Therefore, we should emphasize understanding the molecular pathways that dictate the growth and the metastatic potential of the EAC tumor cells.
The Wnt signaling pathway participates in various stages of embryogenesis and the regulation of various stages of the cell cycle, while its dysregulation has been associated with carcinogenesis in various tumor types. Wnts are secreted glycoproteins with a complex signaling role. Under normal conditions, Wnt glycoproteins lead to dephosphorylation of β-catenin and its subsequent translocation to the nucleus, where it binds to the transcription factors TCF\LEF-1, resulting in the expression of target genes such as Cyclin D1, Axin2, c-MYC, and DKK1 [4].
The Dickkopf (DKK) protein family is one of the five protein families known to act as extracellular Wnt antagonists. It consists of the Dickkopf-1 (DKK1), Dickkopf-2 (DKK2), Dickkopf-3 (DKK3), and Dickkopf-4 (DKK4) proteins, and the Soggy protein (Dkkl1) [5].
DKK proteins are secreted proteins that bind to the transmembrane receptors KREMEN 1 (Krm1) and KREMEN 2 (Krm2) but also to the receptors LRP5 and LRP6. The binding of the DKK1 protein to the LRP5/6 receptors, which are also Wnt co-receptors, leads to the internalization of the complex that is created and, as a consequence, it causes changes in the dephosphorylation of β-catenin [4,5,6] (Figure 1A). Krm2 also seems to form a tertiary complex with DKK1 and LRP6 that leads to LRP6 endocytosis and, thus, inhibition of the b-catenin pathway [5] (Figure 1B). Additionally, the binding of DKK1 to LRP5\6 could also induce Wnt–Frizzled interactions with receptor-like tyrosine kinase, ROR/RYK, which leads to activation of Rac GTPase and consequently JNK activation through the Disheveled (Dvl) protein [7] (Figure 1C).
Despite the fact that the Wnt/β-catenin signaling has been known to drive tumor growth, the members of the DKK family that act as antagonists can also function as tumor inducers [4,8,9] (Table 1).
Taking this fact into account, the DKK1 function seems to be dictated by the receptor setting of the tumor cells. DKK1 will function according to the receptor it will find. Therefore, it is interesting to identify novel receptors that work as the binding receptor for DKK proteins. In addition, immunotherapy is a game changer in oncological treatments, and the role of DKK proteins as an immunomodulator has been supported in several reports. Therefore, it is crucial to review the role of DKK proteins in the tissue response to immunotherapy and reflect on it in the setting of EAC.
The aim of this manuscript is to summarize the current knowledge and the relation between DKK proteins and esophageal adenocarcinoma and discuss future perspectives for the development of novel biomarkers and treatments.

2. DKK and EAC

2.1. DKK Proteins Expression Levels in EAC

DKK1 has been studied both in human specimens and cell lines of esophageal adenocarcinoma [4,36,37,38]. Darlavoix et al. have proved that DKK1 is significantly highly expressed in high-grade dysplasia and EAC compared to Barret esophagus or low-grade dysplasia [36]. DKK1 upregulation was associated with the miR-33a-5p downregulation in esophageal cancer cell lines as well as in human specimens [38]. Lyros et al. have also supported that DKK1 is overexpressed in EAC human specimens and cell cultures of esophageal adenocarcinoma [4,37] and provided evidence that the DKK1 upregulation is enhanced during the sequence of esophageal metaplasia–dysplasia–EAC [37].
On the other hand, the expression of DKK2 was found to be decreased in esophageal adenocarcinoma (EAC) cell lines and even more so in 5-FU-resistant EAC cell lines [39]. Interestingly, DKK2 expression has been correlated with survival outcomes, depending on neoadjuvant treatment status. In patients who did not undergo neoadjuvant treatment, higher DKK2 expression was associated with improved survival. Conversely, in patients who received neoadjuvant treatment, higher DKK2 expression was correlated with worse survival [40]. These findings suggest a dual role of DKK2, possibly influenced by the tumor microenvironment and therapeutic interventions. Additionally, DKK3 expression was found to be elevated in 116 human specimens of EAC but was absent in the EAC cell lines studied [41].

2.2. DKK Proteins Function in EAC

DKK1 was reported to favor tumor growth and metastatic state in EAC. Upregulation of DKK1 in EAC cell lines enhances cancer cell proliferation as well as cell invasion and migration [4]. Reversely, DKK1 knockdown appeared to have a negative impact on cancer cells, proliferation, and migration by enhancing apoptosis [4,38]. Interestingly, this tumor-inducing function of DKK1 in cell lines of esophageal adenocarcinoma was shown to be independent of b-catenin as opposed to esophageal squamous cell lines and Barret esophagus cell lines [4,37]. Consequently, the oncogenic function of DKK1 appears to be Wnt-independent.
Nonetheless, DKK1 was downregulated in negative lymph nodes of patients with esophageal cancer and pN1 compared with negative lymph nodes of pN0 patients [42]. This fact implies that there may be pre-metastatic transcriptional changes in lymph nodes, while it highlights the crucial role of the microenvironment in the function of DKK1.
Similarly, when DKK3 was transferred to EAC cell lines, proliferation, invasion, neoangiogenesis, and chemoresistance were enhanced, while DKK3 overexpression in human specimens was correlated to nodal metastases and pathological stage [41].

2.3. DKK Proteins as Serum Biomarkers in EAC

In the base of DKK1 overexpression in EAC human specimens, Ramirez et al. studied the levels of serum DKK1 in patients with cancer of the esophagus. The serum DKK1 was increased in EAC patients in comparison with the control group, while EAC patients had lower levels of serum DKK1 after neo-adjuvant treatment than those without any treatment prior to surgery. Remarkably, both recurrence rates and median overall survival (OS) were correlated with the serum levels of DKK1 prior to surgery [43]. Another study also demonstrated that higher serum DKK1 levels correlate with higher TNM-staging as well as worse 5-year OS [38]. These data suggest that DKK1 could be a very useful serum biomarker in the clinical setting, and it could be used in decision-making in order to identify high-risk patients with worse tumor biology.

3. DKK Proteins in Correlation with Other Receptors Studied in EAC

3.1. EGFR—Her2

The epidermal growth factor receptor (EGFR) and Her2 are members of the ErbB family of receptors, a subfamily of four closely related receptors of tyrosine kinases: EGFR (ErbB-1), Her2/neu (ErbB-2), Her 3 (ErbB-3), and Her 4 (ErbB-4), whose activation is associated with increased cell proliferation, differentiation, and metastasis.
In EAC, EGFR has been found to be highly expressed and its expression to be associated with increased tumor invasion (pT). EGFR gene amplification has also been associated with a higher stage of the disease, less time to recurrence, and less cancer-specific survival [44]. At the same time, EGFR gene amplification was reported to be more prevalent in the distal esophagus and GEJ cancer than in gastric cancer [44]. Accordingly, EGFR overexpression led to shorter OS, too [45,46], while its expression has been associated with worse pathologic features such as pT, venous and lymphatic invasion, and lymph node metastasis in GEJ adenocarcinomas [47]. Of note, EGFR expression has been found to be altered during the progression from gastroesophageal reflux disease to Barrett esophagus, high-grade dysplasia, and EAC [48,49]. However, till now, there has been no clinical benefit with anti-EGFR treatment in EAC [50], signifying crosstalk signaling pathways that could explain the escaping of EGFR blockage downstream activation.
Her2, also a member of the EGFR family, is also overexpressed in EAC [51,52,53] and has been correlated to the progress from Barrett to EAC [52]. As shown in the ToGA clinical trial, the addition of trastuzumab, a recombinant humanized monoclonal antibody against Her2, to chemotherapy led to improved survival in HER2-positive advanced GEJ adenocarcinoma [54]. Since then, in several clinical trials, trastuzumab has shown efficacy against EAC in combination with chemotherapy, immunotherapy, or bevacizumab in neoadjuvant, adjuvant, or perioperative settings [55,56,57,58,59]. However, other specific anti-Her2 molecules, such as lapatinib, Trastuzumab emtansine (T-DM1), or dual anti-Her2 therapy (pertuzumab and trastuzumab), have not demonstrated similar efficacy against esophageal adenocarcinoma [60,61,62], dictating a more complex downstream signaling pathway activation.
DKK1 overexpression in lung adenocarcinoma has been reported to promote tumor growth and, interestingly, has been linked to resistance to anti-EGFR therapy [63], allowing speculation on a possible role of DKK1 in EGFR downstream activation. The immune status and the expression of immune checkpoints were also correlated with a higher risk of resistance [63], and consequently, DKK1 could promote treatment resistance by acting as an immunomodulator. On the other hand, in breast cancer, cancer cells can develop trastuzumab resistance by downregulating DKK1 and activating the Wnt signaling pathway [64]. To extrapolate, a possible correlation of DKK1 expression with Her2-positive expression in EAC might provide an explanation of Her2 drug resistance or reveal a subgroup of patients that are more prone to respond to target therapies. Such scenarios merit further investigation. However, such a correlation between EGFR or Her2 and DKK1 still needs to be investigated in EAC.

3.2. VEGF—VEGFR-2

Vascular endothelial growth factor (VEGF) has been found to be highly expressed in EAC and GEJ adenocarcinomas [65,66,67], while it was correlated to tumor invasion, too [67]. Serum VEGF was also higher in patients with EAC and is related to worse OS and worrisome pathologic features [68]. However, bevacizumab, a monoclonal antibody against VEGF, did not manage to show a significant effect in EAC [69,70]. In contrast, Ramucirumab, a monoclonal antibody that also acts as a VEGFR-2 antagonist, was found to improve overall survival as well as disease control when used either as monotherapy or combined with chemotherapy as second-line treatment in phase III trials [71,72]. Despite the fact that no such efficacy was proved when used as first-line treatment in patients with metastatic tumors [73], Ramucirumab plus FLOT as a perioperative treatment showed promising efficacy [74]. Apatinib, another molecule that inhibits both VEGFR and Her2, has also shown efficacy in advanced EAC [75]. Those therapeutic effects signify a role for VEGFR in EAC tumor biology, which has, until now, not been clarified.
Expression of DKK1 has been positively correlated with the expression of VEGF in various cancer types. Lower expression of DKK1 in colorectal cancer downregulated VEGF [10], while higher expression of DKK1 was associated with higher expression of VEGF in hepatocellular carcinoma [76] and cholangiocarcinoma [77]. These observations underline the importance of further investigation of the role of DKK proteins in conjunction with VEGFR-mediated pathways in EAC.

3.3. c-MET

c-MET, the hepatocyte growth factor (HGF) receptor, is upregulated in EAC, and it is associated with poorer prognosis and OS [78,79]. Crizotinib, an oral inhibitor of several kinases that inhibits c-MET, too, has shown promising preliminary results when used in patients with upregulated c-MET in phase I studies [80,81]. Nonetheless, the addition of various c-MET inhibitors to chemotherapy did not lead to an improved clinical response in phase II [50,82,83] or III clinical trials [84]. In lung cancer, particularly those with c-Met activation, the pharmaceutical blockade of c-Met resulted in reduced tumor growth via suppression of DKK1 expression [85]. Although no data exists at present, the possible correlation between c-MET and DKK1 in EAC is an attractive field of research.

4. DKK as Immunomodulator

Activation of the Wnt signaling pathway participates in the function of immune cells and T cell and B cell development. In fact, DKK1 has been shown to contribute to the modulation of various immune cell activities, resulting in the enhancement of tumor progression [86]. DKK1 seems to have immunomodulatory effects in the tumor microenvironment, inducing immunosuppression and a low anti-tumor response by impeding a Natural Killer (NK) cell-mediated response and enhancing myeloid-derived suppressor cell activity [87]. DKK1 seems also to affect PDL-1 expression [87,88].
Programmed cell death protein 1 (PD-1) is a receptor on the T cell surface that suppresses lymphocyte activation and immune cell function. Programmed cell death ligand 1 (PDL-1) is overexpressed in various cancers, among them also in esophageal adenocarcinomas, especially in those with microsatellite instability (MSI) [89,90]. In EAC, PDL-1 is also expressed in lymph node metastasis as well as in distant metastasis, and it can be used as a prognostic factor, too [91,92,93,94]. Immunotherapy regimens that bind to PD1 and inhibit ligation to PDL-1 have been approved as treatment options in EAC [95].
Latency-competent cancer (LCC) cells seem to play an important role in cancer progression and metastasis. LCC cells can express DKK1, a transcriptional target of Sox2, to enter a slow-cycling state and act like stem cells. Overexpression of DKK1 results in the downregulation of NK cell-activating ligands and impedes NK cell-mediated clearance of the LCC cells as well [86,96].
Furthermore, DKK1 expression is positively correlated with the accumulation of myeloid-derived suppressor cells (MDSCs) in cancer. Elevated levels of DKK1 also decrease the number of CD8+ T cells, CD45+ leukocytes, and NK cells and impede T cell activation and proliferation [86,97].
DKN-01, an anti-DKK1 antibody, has been studied in combination with pembrolizumab in advanced esophagogastric cancer in a phase I study [87], as well as in combination with tislelizumab [98,99], with promising preliminary results. DKN-01 also plays an immunomodulatory role, demanding the presence of NK cells as well as the unimpeded function of the immune system in order to enhance its anti-tumor activity [100]. At the same time, DKN-01 can lead to the downregulation of MDSCs and upregulation of CD45+ leukocytes [86].
In gastric cancer, inhibition of DKK1-enhanced NK group 2 member D (NKG2D) CAR-T cells’ function by elevating the number of NKG2D ligands [101]. Moreover, in colorectal cancer with impaired mismatch repair, inhibition of DKK1 improved the response to anti-PD-1 therapy by enhancing CD8+ T cell proliferation and function [102].
One of the reasons for inadequate PD-1 responsiveness is the expansion of intra-tumoral MDSCs, which is enhanced by high levels of DKK1. In addition, anti-DKK1 therapy can induce PDL-1 expression on intra-tumoral MDSCs as well as reduce their number [103]. This explains why the combination of anti-DKK1 and anti-PD/PD-L1 therapy seems to have encouraging preliminary results, especially in patients with high expression of DKK1 [87]. Consequently, the combination of anti-DKK1 and anti-PD/PDL-1 therapy could be a possible hallmark in cancer treatment [86,102].
DKK3 seems also to have a crucial role as an immunomodulator. In fact, DKK3 participates in the maturation of B cells, the tolerance of CD8+ T cells, and the differentiation of monocytes to dendritic cells [104]. In various cancers, DKK3 may act as an oncogene through immunomodulation of the tumor microenvironment [104], and it could also explain its oncogenic function in EAC (41).

5. Clinical Trials of DKK1 in EAC

DKK1 has also been studied as a potential target of anti-cancer therapy. DKN-01, an IgG4 monoclonal antibody against DKK1, is being studied in trials as monotherapy or combination therapy in advanced GEJ adenocarcinoma [98] (Table 2).
DKN-01 as monotherapy or in combination with paclitaxel or pembrolizumab in esophagogastric cancer (EGC) has been studied in a phase Ib study (NCT02013154). In preliminary results, the combination of DKN-01 plus paclitaxel demonstrated sufficient anti-tumor activity with a favorable safety profile [105]. At the same time, DKN-01 in combination with pembrolizumab showed a favorable safety profile, while the anti-tumor efficacy was superior mainly in anti-PD-1/PD-L1-naïve patients with high expression of DKK1 [87].
Another phase 2a study of DKN-01 in combination with tislelizumab, an anti-PD-1 antibody, plus CAPOX chemotherapy in Her2-negative advanced gastric or gastroesophageal junction adenocarcinomas (DisTinGuish) showed prolongation of PFS and OS with a favorable safety profile. Among 25 patients receiving first-line treatment, 21 had dictated levels of DKK1, while 22 had dictated levels of PD-L1, with the majority having a low expression of PD-L1, though [98]. DKN-01, in combination with tislelizumab, displayed promising efficacy as a second-line treatment in patients overexpressing DKK1. The most promising and durable results were noticed in DKK1 high/PD-L1 high (vCPS ≥ 10) patients [99]. After these results, in ongoing part C of DisTinGuish trial, 160 Her2negative patients with unresectable, locally advanced, or metastatic disease who have received no prior therapy will be randomized to a 1:1 ratio to receive either DKN-01 in combination with tislelizumab and chemotherapy regimen (CAPOX or mFOLFOX6) (n = 80) or tislelizumab in combination with a chemotherapy regimen (CAPOX or mFOLFOX6) alone (n = 80) [NCT04363801].
Furthermore, DKN-01 is currently studied in combination with atezolizumab in patients with advanced gastroesophageal cancer who have progressed following chemotherapy in a phase II clinical trial [NCT04166721].

6. Potential Receptors for DKK-Mediated Function in EAC: A Novel Interpretation

DKK proteins are known as Wnt antagonists, but it seems that they can also act outside the ordinary Wnt pathway [40]. CKAP4 (cytoskeleton-associated protein 4) has also been proven to be a DKK1 receptor [6,106] and could play a crucial role in this pathway [107,108]. CKAP4 (also named P63, CLIMP-63, and ERGIC-61) is mainly a protein of the endoplasmic reticulum (ER) contributing to the stabilization of ER. A small amount of CKAP4 can also be transferred to the cell surface through the trans-Golgi network, where it acts as a type II transmembrane protein [107,108,109]. In contrast with LRP and Kremen, CKAP4 binds to DKK1 through CRD1, which is a more conserved domain than CRD2 in the DKK family, and as a result, other members of the DKK family could also be ligands of CKAP4 [5,6,106]. In fact, although DKK3 is mainly known as a tumor suppressor, it also binds to CKAP4 through CRD1, acting as an oncogene [110].
After binding to DKK1, CKAP4 activates PI3K (phosphoinositide-3-kinase) through a proline-rich domain, which in turn phosphorylates PIP3 (phosphatidylinositol(3,4,5)-triphosphate) resulting in the activation of intracellular signaling pathways mediated by Akt (protein kinase B) [6,107,109] (Figure 2).
In these pathways, the process of palmitoylation seems to play an important role, as it contributes to the transfer of LRP6 from ER to the cell surface and CKAP4 to the lipid rafts of the cell membrane. Additionally, a ternary complex among DKK1-LRP5\6-CKAP4 seems to enhance the proliferative DKK1-CKAP4 signal [108,109]. DKK1 controls and induces depalmitoylation of LRP5\6 and CKAP4, leading to endocytosis and inactivation of its own receptors [109].
Apart from the various biological processes in which CKAP4 is involved, it also acts as a pro-tumor molecule. It has been shown that binding of DKK1 to CKAP4 leads to cell proliferation, while anti-CKAP4 antibodies seem to have anti-tumor activity [106]. The necessity of the expression of both DKK1 and CKAP4 in tumorigenesis is highlighted by many studies [6,107,111]. DKK1 and CKAP4 were highly expressed in lung adenocarcinoma, pancreatic duct adenocarcinoma as well as esophageal squamous cell carcinoma and, apart from this, the synchronous expression of DKK1 and CKAP4 was correlated to a worse prognosis [6,31,111,112], while other CKAP4 ligands were not involved in cell proliferation of those cancers [6]. Additionally, the use of an anti-CKAP4 antibody or a DKK1 that was unable to bind to CKAP4 impeded EAC cell line growth [110,111,112]. CKAP4 can enhance cell migration independently of DKK1 as well. CKAP4 binding to β1 integrin induces the recycling of α5β1 integrin, and consequently, it reduces the stability of cell adhesion [113].
Given the above, a possible explanation of the diverse roles of DKK proteins in carcinogenesis lies in the biological context in which they are expressed. In fact, we should not interpret the function of DKK proteins as units but in combination with the expression of their receptors in each microenvironment. We should bear in mind that they can act either in a Wnt-dependent manner or in a Wnt-independent manner.
The DKK-CKAP4 axis seems to be involved in the tumorigenesis of EAC independent of Wnt, and it could be a promising molecular pathway that could elucidate the role of DKK1 in EAC even more. DKK1 is increased in tumor specimens of patients with EAC [4,36,37,38]. Additionally, the synchronous expression of both DKK1 and CKAP4 seems to result in a worse prognosis in different types of cancer [6,107,111,112]. Consequently, it seems that the presence of both of these molecules may be the key to their oncogenic function.
DKK3 can also be found increased in EAC [41]. DKK3 was shown to enhance tumorigenesis through the TGFβ pathway, but both Kremen1/2 and CKAP4 can be receptors of DKK3 [41,114]. Although little is known about the role of the other members of the DKK family in EAC, all of them appear to bind to CKAP4 and Kremen1/2 [5,41]. A potential role for them in the carcinogenesis of EAC can be hypothesized.
Although it has not been studied in the serum of patients with EAC, CKAP4 is also secreted into the serum and has been found elevated in various types of cancer. It could, therefore, be used as another serological cancer biomarker [115]. Serum DKK1 is highly elevated in EAC [38,43]. These molecules could prove very useful in the early diagnosis of EAC and serve as valuable pre-therapeutic serologic markers.
Interestingly, targeting the DKK1-CKAP4 pathway could be a significant way to develop novel therapeutic agents. Knockdown of DKK1 or CKAP4 inhibited cell proliferation [4,112], and the anti-CKAP4 antibody seems to suppress tumor formation [112]. Last but not least, DKK1 can elevate PD-L1 expression in a CKAP4-dependent way through the activation of PI3K-Akt signaling [88]. Thus, either DKK1 or CKAP4 could serve as molecular targets for anti-cancer therapy. Several molecules have been studied as anti-DKK1 drugs, and DKN-01 has shown some promising results [87,98]. An anti-CKAP4 antibody, an mi-RNA, or a vaccine could be an alternative [6]. A humanized anti-CKAP4 antibody showed efficacy against pancreatic cancer in murine cancer models by inhibiting the DKK1-CKAP4 axis [116]. CKAP4 could be the ligand to which more than one DKK protein binds. At the same time, CKAP4 may enhance cell migration independently of DKK1 [113]. Finally, the combination of such a targeted therapy with immunotherapy could be a cutting-edge point in the treatment of EAC.
Given the fact that the majority of EAC patients with locally advanced EAC undergo pre-surgical treatments, neoadjuvant regiments could modify the tumor molecular microenvironment. This modulation in the tumor microenvironment could be a reason for poor or inadequate responsiveness in treatment. Expression of DKK2 was shown to be decreased in 5-FU-resistant EAC cell lines [39] as well as correlated with worse survival in patients having received neoadjuvant treatment [40], and DKK3 improved chemoresistance in EAC [41]. Consequently, DKK proteins and their receptors could serve as predictors of response to chemotherapy, although further research is needed in this field.
Further studies in animal models and human specimens are required to enhance our understanding of the exact role of DKK proteins and their possible receptors in EAC. Such an understanding will help the development of possible anti-cancer drugs. According to the data presented in this review, this field is really promising.

7. Conclusions

DKK proteins play a crucial role in EAC, and they are involved in tumorigenesis and disease progression. DKK proteins and their potential receptors could represent valuable prognostic biomarkers and therapeutic targets in EAC. Notably, the potential role of DKK as an immunomodulator could feature novel therapeutic hallmarks in EAC.

Author Contributions

M.D.: Conceptualization, Investigation, Writing—Original Draft, Writing—review & editing. O.L.: Conceptualization, Supervision, Writing—Original Draft, Writing—review & editing. T.S.D.: Resources, Methodology, Visualization. P.S.: Validation, Methodology, Writing—review & editing. E.I.K.: Formal analysis, Supervision, Writing—review & editing. A.M. (Adam Mylonakis): Investigation, Visualization, Software. A.M. (Andreas Mamilos): Resources, Validation, Formal analysis. S.S.: Validation, Writing—review & editing. D.S.: Conceptualization, Project administration, Supervision, Writing—review & editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  2. Sheikh, M.; Roshandel, G.; McCormack, V.; Malekzadeh, R. Current Status and Future Prospects for Esophageal Cancer. Cancers 2023, 15, 765. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  3. SEER; National Cancer Institute; Bethesda, M.D. Cancer Stat Facts: Esophageal Cancer. Available online: https://seer.cancer.gov/statfacts/html/esoph.html (accessed on 1 September 2024).
  4. Lyros, O.; Lamprecht, A.K.; Nie, L.; Thieme, R.; Götzel, K.; Gasparri, M.; Haasler, G.; Rafiee, P.; Shaker, R.; Gockel, I. Dickkopf-1 (DKK1) promotes tumor growth via Akt-phosphorylation and independently of Wnt-axis in Barrett’s associated esophageal adenocarcinoma. Am. J. Cancer Res. 2019, 9, 330–346. [Google Scholar] [PubMed] [PubMed Central]
  5. Niehrs, C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene 2006, 25, 7469–7481. [Google Scholar] [CrossRef] [PubMed]
  6. Kimura, H.; Fumoto, K.; Shojima, K.; Nojima, S.; Osugi, Y.; Tomihara, H.; Eguchi, H.; Shintani, Y.; Endo, H.; Inoue, M.; et al. CKAP4 is a Dickkopf1 receptor and is involved in tumor progression. J. Clin. Investig. 2016, 126, 2689–2705. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  7. Jiang, H.; Zhang, Z.; Yu, Y.; Chu, H.Y.; Yu, S.; Yao, S.; Zhang, G.; Zhang, B.T. Drug Discovery of DKK1 Inhibitors. Front. Pharmacol. 2022, 13, 847387. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  8. Mazon, M.; Masi, D.; Carreau, M. Modulating Dickkopf-1: A Strategy to Monitor or Treat Cancer? Cancers 2016, 8, 62. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  9. Liu, Y.; Tang, W.; Xie, L.; Wang, J.; Deng, Y.; Peng, Q.; Zhai, L.; Li, S.; Qin, X. Prognostic significance of dickkopf-1 overexpression in solid tumors: A meta-analysis. Tumor Biol. 2014, 35, 3145–3154. [Google Scholar] [CrossRef] [PubMed]
  10. Liu, Z.; Sun, B.; Qi, L.; Li, Y.; Zhao, X.; Zhang, D.; Zhang, Y. Dickkopf-1 expression is down-regulated during the colorectal adenoma-carcinoma sequence and correlates with reduced microvessel density and VEGF expression. Histopathology 2015, 67, 158–166. [Google Scholar] [CrossRef] [PubMed]
  11. Qi, L.; Sun, B.; Liu, Z.; Li, H.; Gao, J.; Leng, X. Dickkopf-1 inhibits epithelial-mesenchymal transition of colon cancer cells and contributes to colon cancer suppression. Cancer Sci. 2012, 103, 828–835. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  12. Aguilera, Ó.; González-Sancho, J.M.; Zazo, S.; Rincón, R.; Fernández, A.F.; Tapia, O.; Canals, F.; Morte, B.; Calvanese, V.; Orgaz, J.L.; et al. Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer. Oncotarget 2015, 6, 5903–5917. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  13. Gurluler, E.; Tumay, L.V.; Guner, O.S.; Kucukmetin, N.T.; Hizli, B.; Zorluoglu, A. The role of preoperative serum levels for Dickkopf-related protein 1 as a potential marker of tumor invasion in patients with stage II and III colon cancer. Eur. Rev. Med. Pharmacol. Sci. 2014, 18, 1742–1747. [Google Scholar] [PubMed]
  14. Yu, B.; Yang, X.; Xu, Y.; Yao, G.; Shu, H.; Lin, B.; Hood, L.; Wang, H.; Yang, S.; Gu, J.; et al. Elevated expression of DKK1 is associated with cytoplasmic/nuclear beta-catenin accumulation and poor prognosis in hepatocellular carcinomas. J. Hepatol. 2009, 50, 948–957. [Google Scholar] [CrossRef] [PubMed]
  15. Yang, H.; Chen, G.D.; Fang, F.; Liu, Z.; Lau, S.H.; Zhang, J.F.; Lau, W.Y.; Yang, L.Y. Dickkopf-1: As a diagnostic and prognostic serum marker for early hepatocellular carcinoma. Int. J. Biol. Markers 2013, 28, 286–297. [Google Scholar] [CrossRef]
  16. Tung, E.K.; Mak, C.K.; Fatima, S.; Lo, R.C.; Zhao, H.; Zhang, C.; Dai, H.; Poon, R.T.; Yuen, M.F.; Lai, C.L.; et al. Clinicopathological and prognostic significance of serum and tissue dickkopf-1 levels in human hepatocellular carcinoma. Liver Int. 2011, 31, 1494–1504. [Google Scholar] [CrossRef]
  17. Tao, Y.M.; Liu, Z.; Liu, H.L. Dickkopf-1 (dkk1) promotes invasion and metastasis of hepatocellular carcinoma. Dig. Liver Dis. J. Ital. Soc. Gastroenterol. Ital. Assoc. Study Liver 2013, 45, 251–257. [Google Scholar] [CrossRef]
  18. Lee, H.S.; Lee, H.E.; Park, D.J.; Kim, H.H.; Kim, W.H.; Park, K.U. Clinical significance of serum and tissue Dickkopf-1 levels in patients with gastric cancer. Clin. Chim. Acta 2012, 413, 1753–1760. [Google Scholar] [CrossRef] [PubMed]
  19. Liu, Q.R.; Li, Y.F.; Deng, Z.Q.; Cao, J.Q. Prognostic Significance of Dickkopf-1 in Gastric Cancer Survival: A Meta-Analysis. Genet. Test Mol. Biomark. 2016, 20, 170–175. [Google Scholar] [CrossRef] [PubMed]
  20. Wang, S.; Zhang, S. Dickkopf-1 is frequently overexpressed in ovarian serous carcinoma and involved in tumor invasion. Clin. Exp. Metastasis 2011, 28, 581–591. [Google Scholar] [CrossRef] [PubMed]
  21. Klotz, D.M.; Link, T.; Goeckenjan, M.; Wimberger, P.; Poetsch, A.R.; Jaschke, N.; Hofbauer, L.C.; Göbel, A.; Rachner, T.D.; Kuhlmann, J.D. Evaluation of circulating Dickkopf-1 as a prognostic biomarker in ovarian cancer patients. Clin. Chem. Lab. Med. 2021, 60, 109–117. [Google Scholar] [CrossRef] [PubMed]
  22. Shizhuo, W.; Tao, J.; Shulan, Z.; Bing, Z. The expression and significance of Dickkopf-1 in epithelial ovarian carcinoma. Int. J. Biol. Markers 2009, 24, 165–170. [Google Scholar] [CrossRef] [PubMed]
  23. Xu, W.H.; Liu, Z.B.; Yang, C.; Qin, W.; Shao, Z.M. Expression of dickkopf-1 and beta-catenin related to the prognosis of breast cancer patients with triple negative phenotype. PLoS ONE 2012, 7, e37624, Erratum in PLoS ONE 2014, 9, e102404. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  24. Zhou, S.J.; Zhuo, S.R.; Yang, X.Q.; Qin, C.X.; Wang, Z.L. Serum Dickkopf-1 expression level positively correlates with a poor prognosis in breast cancer. Diagn. Pathol. 2014, 9, 161. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  25. Dong, L.L.; Qu, L.Y.; Chu, L.Y.; Zhang, X.H.; Liu, Y.H. Serum level of DKK-1 and its prognostic potential in non-small cell lung cancer. Diagn. Pathol. 2014, 9, 52. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  26. Yamabuki, T.; Takano, A.; Hayama, S.; Ishikawa, N.; Kato, T.; Miyamoto, M.; Ito, T.; Ito, H.; Miyagi, Y.; Nakayama, H.; et al. Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas. Cancer Res. 2007, 67, 2517–2525. [Google Scholar] [CrossRef] [PubMed]
  27. Sheng, S.L.; Huang, G.; Yu, B.; Qin, W.X. Clinical significance and prognostic value of serum Dickkopf-1 concentrations in patients with lung cancer. Clin. Chem. 2009, 55, 1656–1664. [Google Scholar] [CrossRef] [PubMed]
  28. Begenik, H.; Kemik, A.S.; Emre, H.; Dulger, A.C.; Demirkiran, D.; Ebinc, S.; Kemik, O. The association between serum Dickkopf-1 levels and esophageal squamous cell carcinoma. Hum. Exp. Toxicol. 2014, 33, 785–788. [Google Scholar] [CrossRef] [PubMed]
  29. Peng, Y.H.; Xu, Y.W.; Guo, H.; Huang, L.S.; Tan, H.Z.; Hong, C.Q.; Li, S.S.; Xu, L.Y.; Li, E.M. Combined detection of serum Dickkopf-1 and its autoantibodies to diagnose esophageal squamous cell carcinoma. Cancer Med. 2016, 5, 1388–1396. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  30. Makino, T.; Yamasaki, M.; Takemasa, I.; Takeno, A.; Nakamura, Y.; Miyata, H.; Takiguchi, S.; Fujiwara, Y.; Matsuura, N.; Mori, M.; et al. Dickkopf-1 expression as a marker for predicting clinical outcome in esophageal squamous cell carcinoma. Ann. Surg. Oncol. 2009, 16, 2058–2064. [Google Scholar] [CrossRef] [PubMed]
  31. Kimura, H.; Sada, R.; Takada, N.; Harada, A.; Doki, Y.; Eguchi, H.; Yamamoto, H.; Kikuchi, A. The Dickkopf1 and FOXM1 positive feedback loop promotes tumor growth in pancreatic and esophageal cancers. Oncogene 2021, 40, 4486–4502. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  32. Shen, C.-H.; Hsieh, H.-Y.; Wang, Y.-H.; Chen, S.-Y.; Tung, C.-L.; Wu, J.-D.; Lin, C.-T.; Chan, M.W.-Y.; Hsu, C.-D.; Chang, D. High dickkopf-1 expression is associated with poor prognosis in patients with advanced urothelial carcinoma. Exp. Ther. Med. 2010, 1, 893–898. [Google Scholar] [CrossRef]
  33. Sun, D.K.; Wang, L.; Wang, J.M.; Zhang, P. Serum Dickkopf-1 levels as a clinical and prognostic factor in patients with bladder cancer. Genet. Mol. Res. 2015, 14, 18181–18187. [Google Scholar] [CrossRef] [PubMed]
  34. Takahashi, N.; Fukushima, T.; Yorita, K.; Tanaka, H.; Chijiiwa, K.; Kataoka, H. Dickkopf-1 is overexpressed in human pancreatic ductal adenocarcinoma cells and is involved in invasive growth. Int. J. Cancer 2010, 126, 1611–1620. [Google Scholar] [CrossRef] [PubMed]
  35. Liu, D.J.; Xie, Y.X.; Liu, X.X.; Huo, Y.M.; Yang, M.W.; Fu, X.L.; Liu, W.; Yang, J.Y.; Li, J.; Hua, R.; et al. The role of Dickkopf-1 as a potential prognostic marker in pancreatic ductal adenocarcinoma. Cell Cycle 2017, 16, 1622–1629. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  36. Darlavoix, T.; Seelentag, W.; Yan, P.; Bachmann, A.; Bosman, F.T. Altered expression of CD44 and DKK1 in the progression of Barrett’s esophagus to esophageal adenocarcinoma. Virchows Arch. 2009, 454, 629–637. [Google Scholar] [CrossRef] [PubMed]
  37. Lyros, O.; Rafiee, P.; Nie, L.; Medda, R.; Jovanovic, N.; Otterson, M.F.; Behmaram, B.; Gockel, I.; Mackinnon, A.; Shaker, R. Wnt/β-Catenin Signaling Activation beyond Robust Nuclear β-Catenin Accumulation in Nondysplastic Barrett’s Esophagus: Regulation via Dickkopf-1. Neoplasia 2015, 17, 598–611. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  38. Song, Q.; Liu, H.; Li, C.; Liang, H. miR-33a-5p inhibits the progression of esophageal cancer through the DKK1-mediated Wnt/β-catenin pathway. Aging 2021, 13, 20481–20494. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  39. Wang, Y.; Zhao, Y.; Herbst, A.; Kalinski, T.; Qin, J.; Wang, X.; Jiang, Z.; Benedix, F.; Franke, S.; Wartman, T.; et al. miR-221 Mediates Chemoresistance of Esophageal Adenocarcinoma by Direct Targeting of DKK2 Expression. Ann. Surg. 2016, 264, 804–814. [Google Scholar] [CrossRef] [PubMed]
  40. Schiffmann, L.M.; Loeser, H.; Jacob, A.S.; Maus, M.; Fuchs, H.; Zhao, Y.; Tharun, L.; Essakly, A.; Iannos Damanakis, A.; Zander, T.; et al. Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma. Cancers 2020, 12, 451. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  41. Wang, Z.; Lin, L.; Thomas, D.G.; Nadal, E.; Chang, A.C.; Beer, D.G.; Lin, J. The role of Dickkopf-3 overexpression in esophageal adenocarcinoma. J. Thorac. Cardiovasc. Surg. 2015, 150, 377–385.e2. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  42. Otto, B.; Koenig, A.M.; Tolstonog, G.V.; Jeschke, A.; Klaetschke, K.; Vashist, Y.K.; Wicklein, D.; Wagener, C.; Izbicki, J.R.; Streichert, T. Molecular changes in pre-metastatic lymph nodes of esophageal cancer patients. PLoS ONE 2014, 9, e102552. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  43. Ramirez, J.G.; Smit, D.J.; Viol, F.; Schrader, J.; Ghadban, T.; Pantel, K.; Izbicki, J.R.; Reeh, M. High Serum Levels of Wnt Signaling Antagonist Dickkopf-Related Protein 1 Are Associated with Impaired Overall Survival and Recurrence in Esophageal Cancer Patients. Cancers 2021, 13, 4980. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  44. Birkman, E.M.; Ålgars, A.; Lintunen, M.; Ristamäki, R.; Sundström, J.; Carpén, O. EGFR gene amplification is relatively common and associates with outcome in intestinal adenocarcinoma of the stomach, gastro-oesophageal junction and distal oesophagus. BMC Cancer 2016, 16, 406. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  45. Hedner, C.; Borg, D.; Nodin, B.; Karnevi, E.; Jirström, K.; Eberhard, J. Expression and Prognostic Significance of Human Epidermal Growth Factor Receptors 1 and 3 in Gastric and Esophageal Adenocarcinoma. PLoS ONE 2016, 11, e0148101. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  46. Liao, J.B.; Lee, H.P.; Fu, H.T.; Lee, H.S. Assessment of EGFR and ERBB2 (HER2) in Gastric and Gastroesophageal Carcinomas: EGFR Amplification is Associated with a Worse Prognosis in Early Stage and Well to Moderately Differentiated Carcinoma. Appl. Immunohistochem. Mol. Morphol. 2018, 26, 374–382. [Google Scholar] [CrossRef] [PubMed]
  47. Aratani, K.; Komatsu, S.; Ichikawa, D.; Ohashi, T.; Miyamae, M.; Okajima, W.; Imamura, T.; Kiuchi, J.; Nishibeppu, K.; Kosuga, T.; et al. Overexpression of EGFR as an Independent Prognostic Factor in Adenocarcinoma of the Esophagogastric Junction. Anticancer Res. 2017, 37, 3129–3135. [Google Scholar] [CrossRef] [PubMed]
  48. Cronin, J.; McAdam, E.; Danikas, A.; Tselepis, C.; Griffiths, P.; Baxter, J.; Thomas, L.; Manson, J.; Jenkins, G. Epidermal growth factor receptor (EGFR) is overexpressed in high-grade dysplasia and adenocarcinoma of the esophagus and may represent a biomarker of histological progression in Barrett’s esophagus (BE). Am. J. Gastroenterol. 2011, 106, 46–56. [Google Scholar] [CrossRef] [PubMed]
  49. Pretto, G.; Gurski, R.R.; Binato, M.; Navarini, D.; Aguiar, W.W.; Meurer, L. Increase of epidermal growth factor receptor expression in progression of GERD, Barrett, and adenocarcinoma of esophagus. Dig. Dis. Sci. 2013, 58, 115–122. [Google Scholar] [CrossRef] [PubMed]
  50. Malka, D.; François, E.; Penault-Llorca, F.; Castan, F.; Bouché, O.; Bennouna, J.; Ghiringhelli, F.; de la Fouchardière, C.; Borg, C.; Samalin, E.; et al. FOLFOX alone or combined with rilotumumab or panitumumab as first-line treatment for patients with advanced gastroesophageal adenocarcinoma (PRODIGE 17-ACCORD 20-MEGA): A randomised, open-label, three-arm phase II trial. Eur. J. Cancer 2019, 115, 97–106. [Google Scholar] [CrossRef] [PubMed]
  51. Rima, F.A.; Hussain, M.; Haque, N.; Dewan, R.K.; Rahman, N.; Jinnah, M.A.; Jeba, R.; Chowdhury, F. HER2 status in Gastric and Gastroesophageal Junction Adenocarcinoma. Mymensingh Med. J. 2017, 26, 372–379. [Google Scholar] [PubMed]
  52. Almhanna, K.; Rosa, M.; Henderson-Jackson, E.; Jiang, K.; Shamekh, R.; Sayegh, Z.; Malafa, M.P.; Coppola, D. Her-2 Expression in Gastroesophageal Intestinal Metaplasia, Dysplasia, and Adenocarcinoma. Appl. Immunohistochem. Mol. Morphol. 2016, 24, 633–638. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  53. Plum, P.S.; Gebauer, F.; Krämer, M.; Alakus, H.; Berlth, F.; Chon, S.H.; Schiffmann, L.; Zander, T.; Büttner, R.; Hölscher, A.H.; et al. HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma. BMC Cancer 2019, 19, 38. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  54. Bang, Y.J.; Van Cutsem, E.; Feyereislova, A.; Chung, H.C.; Shen, L.; Sawaki, A.; Lordick, F.; Ohtsu, A.; Omuro, Y.; Satoh, T.; et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010, 376, 687–697, Erratum in Lancet 2010, 376, 1302. [Google Scholar] [CrossRef] [PubMed]
  55. Janjigian, Y.Y.; Maron, S.B.; Chatila, W.K.; Millang, B.; Chavan, S.S.; Alterman, C.; Chou, J.F.; Segal, M.F.; Simmons, M.Z.; Momtaz, P.; et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: An open-label, single-arm, phase 2 trial. Lancet Oncol. 2020, 21, 821–831. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  56. Rivera, F.; Izquierdo-Manuel, M.; García-Alfonso, P.; Martínez de Castro, E.; Gallego, J.; Limón, M.L.; Alsina, M.; López, L.; Galán, M.; Falcó, E.; et al. Perioperative trastuzumab, capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or gastro-oesophageal junction adenocarcinoma: NEOHX phase II trial. Eur. J. Cancer 2021, 145, 158–167. [Google Scholar] [CrossRef] [PubMed]
  57. Hofheinz, R.D.; Hegewisch-Becker, S.; Kunzmann, V.; Thuss-Patience, P.; Fuchs, M.; Homann, N.; Graeven, U.; Schulte, N.; Merx, K.; Pohl, M.; et al. Trastuzumab in combination with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel as perioperative treatment for patients with human epidermal growth factor receptor 2-positive locally advanced esophagogastric adenocarcinoma: A phase II trial of the Arbeitsgemeinschaft Internistische Onkologie Gastric Cancer Study Group. Int. J. Cancer 2021, 149, 1322–1331. [Google Scholar] [CrossRef] [PubMed]
  58. Abali, H.; Yalcin, S.; Onal, H.C.; Dane, F.; Oksuzoglu, B.; Ozdemir, N.; Mertsoylu, H.; Artac, M.; Camci, C.; Karabulut, B.; et al. A Phase II Study of the Combination of Oxaliplatin, Capecitabine, and Trastuzumab and Chemoradiotherapy in the Adjuvant Setting in Operated Patients with HER2-positive Gastric or Gastroesophageal Junction Cancer (TOXAG Study): A Turkish Oncology Group Study. Am. J. Clin. Oncol. 2021, 44, 301–307. [Google Scholar] [CrossRef] [PubMed]
  59. Meulendijks, D.; Beerepoot, L.V.; Boot, H.; de Groot, J.W.; Los, M.; Boers, J.E.; Vanhoutvin, S.A.; Polee, M.B.; Beeker, A.; Portielje, J.E.; et al. Trastuzumab and bevacizumab combined with docetaxel, oxaliplatin and capecitabine as first-line treatment of advanced HER2-positive gastric cancer: A multicenter phase II study. Investig. New Drugs 2016, 34, 119–128. [Google Scholar] [CrossRef] [PubMed]
  60. Tabernero, J.; Hoff, P.M.; Shen, L.; Ohtsu, A.; Shah, M.A.; Cheng, K.; Song, C.; Wu, H.; Eng-Wong, J.; Kim, K.; et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): Final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018, 19, 1372–1384. [Google Scholar] [CrossRef] [PubMed]
  61. Hecht, J.R.; Bang, Y.J.; Qin, S.K.; Chung, H.C.; Xu, J.M.; Park, J.O.; Jeziorski, K.; Shparyk, Y.; Hoff, P.M.; Sobrero, A.; et al. Lapatinib in Combination with Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC--A Randomized Phase III Trial. J. Clin. Oncol. 2016, 34, 443–451. [Google Scholar] [CrossRef] [PubMed]
  62. Thuss-Patience, P.C.; Shah, M.A.; Ohtsu, A.; Van Cutsem, E.; Ajani, J.A.; Castro, H.; Mansoor, W.; Chung, H.C.; Bodoky, G.; Shitara, K.; et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): An international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017, 18, 640–653. [Google Scholar] [CrossRef] [PubMed]
  63. Zhuge, J.; Wang, X.; Li, J.; Wang, T.; Wang, H.; Yang, M.; Dong, W.; Gao, Y. Construction of the model for predicting prognosis by key genes regulating EGFR-TKI resistance. Front. Genet. 2022, 13, 968376. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  64. Moon, S.J.; Choi, H.J.; Kye, Y.H.; Jeong, G.Y.; Kim, H.Y.; Myung, J.K.; Kong, G. CTTN Overexpression Confers Cancer Stem Cell-like Properties and Trastuzumab Resistance via DKK-1/WNT Signaling in HER2 Positive Breast Cancer. Cancers 2023, 15, 1168. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  65. Angelescu, C.; Burada, F.; Ioana, M.; Angelescu, R.; Moraru, E.; Riza, A.; Marchian, S.; Mixich, F.; Cruce, M.; Săftoiu, A. VEGF-A and VEGF-B mRNA expression in gastro-oesophageal cancers. Clin. Transl. Oncol. 2013, 15, 313–320. [Google Scholar] [CrossRef] [PubMed]
  66. Gray, R.T.; O’Donnell, M.E.; Maxwell, P.; McGuigan, J.A.; Spence, G.M. Long-term follow-up of immunocytochemical analysis of vascular endothelial growth factor (VEGF), and its two receptors, VEGF-R1 (Flt-1) and VEGF-R2 (Flk-1/KDR), in oesophagogastric cancer. Int. J. Biol. Markers 2013, 28, 63–70. [Google Scholar] [CrossRef] [PubMed]
  67. Takala, H.; Saarnio, J.; Wiik, H.; Ohtonen, P.; Soini, Y. HIF-1α and VEGF are associated with disease progression in esophageal carcinoma. J. Surg. Res. 2011, 167, 41–48. [Google Scholar] [CrossRef] [PubMed]
  68. Kozłowski, M.; Laudański, W.; Mroczko, B.; Szmitkowski, M.; Milewski, R.; Łapuć, G. Serum tissue inhibitor of metalloproteinase 1 (TIMP-1) and vascular endothelial growth factor A (VEGF-A) are associated with prognosis in esophageal cancer patients. Adv. Med. Sci. 2013, 58, 227–234. [Google Scholar] [CrossRef] [PubMed]
  69. Ku, G.Y.; Bains, M.S.; Park, D.J.; Janjigian, Y.Y.; Rusch, V.W.; Rizk, N.P.; Yoon, S.S.; Millang, B.; Capanu, M.; Goodman, K.A.; et al. Phase II study of bevacizumab and preoperative chemoradiation for esophageal adenocarcinoma. J. Gastrointest. Oncol. 2016, 7, 828–837. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  70. Cunningham, D.; Stenning, S.P.; Smyth, E.C.; Okines, A.F.; Allum, W.H.; Rowley, S.; Stevenson, L.; Grabsch, H.I.; Alderson, D.; Crosby, T.; et al. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): Primary analysis results of a multicentre, open-label, randomised phase 2–3 trial. Lancet Oncol. 2017, 18, 357–370. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  71. Fuchs, C.S.; Tomasek, J.; Yong, C.J.; Dumitru, F.; Passalacqua, R.; Goswami, C.; Safran, H.; Dos Santos, L.V.; Aprile, G.; Ferry, D.R.; et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): An international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014, 383, 31–39. [Google Scholar] [CrossRef] [PubMed]
  72. Wilke, H.; Muro, K.; Van Cutsem, E.; Oh, S.C.; Bodoky, G.; Shimada, Y.; Hironaka, S.; Sugimoto, N.; Lipatov, O.; Kim, T.Y.; et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol. 2014, 15, 1224–1235. [Google Scholar] [CrossRef] [PubMed]
  73. Fuchs, C.S.; Shitara, K.; Di Bartolomeo, M.; Lonardi, S.; Al-Batran, S.E.; Van Cutsem, E.; Ilson, D.H.; Alsina, M.; Chau, I.; Lacy, J.; et al. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): A double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019, 20, 420–435, Erratum in Lancet Oncol. 2019, 20, e242. [Google Scholar] [CrossRef] [PubMed]
  74. Goetze, T.O.; Hofheinz, R.D.; Gaiser, T.; Schmalenberg, H.; Strumberg, D.; Goekkurt, E.; Angermeier, S.; Zander, T.; Kopp, H.G.; Pink, D.; et al. Perioperative FLOT plus ramucirumab for resectable esophagogastric adenocarcinoma: A randomized phase II/III trial of the German AIO and Italian GOIM. Int. J. Cancer 2023, 153, 153–163. [Google Scholar] [CrossRef] [PubMed]
  75. Yanwei, L.; Feng, H.; Ren, P.; Yue, J.; Zhang, W.; Tang, P.; Shang, X.; Pang, Q.; Liu, D.; Chen, C.; et al. Safety and Efficacy of Apatinib Monotherapy for Unresectable, Metastatic Esophageal Cancer: A Single-Arm, Open-Label, Phase II Study. Oncologist 2020, 25, e1464–e1472. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  76. Seo, S.H.; Cho, K.J.; Park, H.J.; Kim, H.; Lee, H.W.; Kim, B.K.; Park, J.Y.; Kim, D.Y.; Ahn, S.H.; Kim, S.U. Dickkopf-1 promotes angiogenesis by upregulating VEGF receptor 2-mediated mTOR/p70S6K signaling in hepatocellular carcinoma. Am. J. Cancer Res. 2021, 11, 4788–4806. [Google Scholar] [PubMed] [PubMed Central]
  77. Shi, R.Y.; Yang, X.R.; Shen, Q.J.; Yang, L.X.; Xu, Y.; Qiu, S.J.; Sun, Y.F.; Zhang, X.; Wang, Z.; Zhu, K.; et al. High expression of Dickkopf-related protein 1 is related to lymphatic metastasis and indicates poor prognosis in intrahepatic cholangiocarcinoma patients after surgery. Cancer 2013, 119, 993–1003. [Google Scholar] [CrossRef] [PubMed]
  78. Ren, J.L.; Wu, H.F.; Wang, W.J.; Hu, G.M.; Gu, B.; Zhang, M.; Wang, Y.X. C-Met as a potential novel prognostic marker in squamous cell carcinoma and adenocarcinoma of esophagus: Evidence from a meta-analysis. Panminerva Med. 2017, 59, 97–106. [Google Scholar] [CrossRef] [PubMed]
  79. Catenacci, D.V.; Ang, A.; Liao, W.L.; Shen, J.; O’Day, E.; Loberg, R.D.; Cecchi, F.; Hembrough, T.; Ruzzo, A.; Graziano, F. MET tyrosine kinase receptor expression and amplification as prognostic biomarkers of survival in gastroesophageal adenocarcinoma. Cancer 2017, 123, 1061–1070. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  80. Lennerz, J.K.; Kwak, E.L.; Ackerman, A.; Michael, M.; Fox, S.B.; Bergethon, K.; Lauwers, G.Y.; Christensen, J.G.; Wilner, K.D.; Haber, D.A.; et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J. Clin. Oncol. 2011, 29, 4803–4810. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  81. Aparicio, T.; Cozic, N.; de la Fouchardière, C.; Meriaux, E.; Plaza, J.; Mineur, L.; Guimbaud, R.; Samalin, E.; Mary, F.; Lecomte, T.; et al. The Activity of Crizotinib in Chemo-Refractory MET-Amplified Esophageal and Gastric Adenocarcinomas: Results from the AcSé-Crizotinib Program. Target Oncol. 2021, 16, 381–388. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  82. Shah, M.A.; Cho, J.Y.; Tan, I.B.; Tebbutt, N.C.; Yen, C.J.; Kang, A.; Shames, D.S.; Bu, L.; Kang, Y.K. A Randomized Phase II Study of FOLFOX with or Without the MET Inhibitor Onartuzumab in Advanced Adenocarcinoma of the Stomach and Gastroesophageal Junction. Oncologist 2016, 21, 1085–1090. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  83. Pant, S.; Patel, M.; Kurkjian, C.; Hemphill, B.; Flores, M.; Thompson, D.; Bendell, J. A Phase II Study of the c-Met Inhibitor Tivantinib in Combination with FOLFOX for the Treatment of Patients with Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction, or Stomach. Cancer Investig. 2017, 35, 463–472. [Google Scholar] [CrossRef] [PubMed]
  84. Catenacci, D.V.T.; Tebbutt, N.C.; Davidenko, I.; Murad, A.M.; Al-Batran, S.E.; Ilson, D.H.; Tjulandin, S.; Gotovkin, E.; Karaszewska, B.; Bondarenko, I.; et al. Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017, 18, 1467–1482. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  85. Zhang, P.; Li, S.; Lv, C.; Si, J.; Xiong, Y.; Ding, L.; Ma, Y.; Yang, Y. BPI-9016M, a c-Met inhibitor, suppresses tumor cell growth, migration and invasion of lung adenocarcinoma via miR203-DKK1. Theranostics 2018, 8, 5890–5902. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  86. Chu, H.Y.; Chen, Z.; Wang, L.; Zhang, Z.K.; Tan, X.; Liu, S.; Zhang, B.T.; Lu, A.; Yu, Y.; Zhang, G. Dickkopf-1: A Promising Target for Cancer Immunotherapy. Front. Immunol. 2021, 12, 658097. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  87. Klempner, S.J.; Bendell, J.C.; Villaflor, V.M.; Tenner, L.L.; Stein, S.M.; Rottman, J.B.; Naik, G.S.; Sirard, C.A.; Kagey, M.H.; Chaney, M.F.; et al. Safety, Efficacy, and Biomarker Results from a Phase Ib Study of the Anti-DKK1 Antibody DKN-01 in Combination with Pembrolizumab in Advanced Esophagogastric Cancers. Mol. Cancer Ther. 2021, 20, 2240–2249. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  88. Yang, R.H.; Qin, J.; Cao, J.L.; Zhang, M.Z.; Li, Y.Y.; Wang, M.Q.; Fang, D.; Xie, S.Q. Dickkopf-1 drives tumor immune evasion by inducing PD-L1 expression in hepatocellular carcinoma. Biochem. Pharmacol. 2023, 208, 115378. [Google Scholar] [CrossRef] [PubMed]
  89. Teixeira Farinha, H.; Digklia, A.; Schizas, D.; Demartines, N.; Schäfer, M.; Mantziari, S. Immunotherapy for Esophageal Cancer: State-of-the Art in 2021. Cancers 2022, 14, 554. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  90. Yoshida, T.; Ogura, G.; Tanabe, M.; Hayashi, T.; Ohbayashi, C.; Azuma, M.; Kunisaki, C.; Akazawa, Y.; Ozawa, S.; Matsumoto, S.; et al. Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan. Cancer Biol. Ther. 2022, 23, 191–200. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  91. Dislich, B.; Stein, A.; Seiler, C.A.; Kröll, D.; Berezowska, S.; Zlobec, I.; Galvan, J.; Slotta-Huspenina, J.; Walch, A.; Langer, R. Expression patterns of programmed death-ligand 1 in esophageal adenocarcinomas: Comparison between primary tumors and metastases. Cancer Immunol. Immunother. 2017, 66, 777–786. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  92. Knief, J.; Lazar-Karsten, P.; Hummel, R.; Wellner, U.; Thorns, C. PD-L1 expression in carcinoma of the esophagogastric junction is positively correlated with T-cell infiltration and overall survival. Pathol. Res. Pract. 2019, 215, 152402. [Google Scholar] [CrossRef] [PubMed]
  93. Okadome, K.; Baba, Y.; Nomoto, D.; Yagi, T.; Kalikawe, R.; Harada, K.; Hiyoshi, Y.; Nagai, Y.; Ishimoto, T.; Iwatsuki, M.; et al. Prognostic and clinical impact of PD-L2 and PD-L1 expression in a cohort of 437 oesophageal cancers. Br. J. Cancer 2020, 122, 1535–1543. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  94. Yagi, T.; Baba, Y.; Ishimoto, T.; Iwatsuki, M.; Miyamoto, Y.; Yoshida, N.; Watanabe, M.; Baba, H. PD-L1 Expression, Tumor-infiltrating Lymphocytes, and Clinical Outcome in Patients with Surgically Resected Esophageal Cancer. Ann. Surg. 2019, 269, 471–478. [Google Scholar] [CrossRef] [PubMed]
  95. Shah, M.A.; Kennedy, E.B.; Alarcon-Rozas, A.E.; Alcindor, T.; Bartley, A.N.; Malowany, A.B.; Bhadkamkar, N.A.; Deighton, D.C.; Janjigian, Y.; Karippot, A.; et al. Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline. J. Clin. Oncol. 2023, 41, 1470–1491, Erratum in J. Clin. Oncol. 2023, JCO2300441. [Google Scholar] [CrossRef] [PubMed]
  96. Malladi, S.; Macalinao, D.G.; Jin, X.; He, L.; Basnet, H.; Zou, Y.; de Stanchina, E.; Massagué, J. Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell 2016, 165, 45–60. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  97. D’Amico, L.; Mahajan, S.; Capietto, A.H.; Yang, Z.; Zamani, A.; Ricci, B.; Bumpass, D.B.; Meyer, M.; Su, X.; Wang-Gillam, A.; et al. Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer. J. Exp. Med. 2016, 213, 827–840. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  98. Klempner, S.J.; Sonbol, B.B.; Wainberg, Z.A.; Uronis, H.E.; Chiu, V.K.; Scott, A.J.; Iqbal, S.; Tejani, M.A.; Stilian, M.C.; Thoma, M.; et al. A phase 2 study (DisTinGuish) of DKN-01 in combination with tislelizumab + chemotherapy as first-line (1L) therapy in patients with advanced gastric or GEJ adenocarcinoma (GEA). J. Clin. Oncol. 2023, 41, 4027. [Google Scholar] [CrossRef]
  99. Klempner, S.; Ajani, J.; Chao, J.; Uronis, H.; Sirard, C.; Kagey, M.; Baum, J.; Zhang, L.; Kim, I.H.; Oh, D.Y.; et al. 553 DKN-01 and tislelizumab as a second-line (2L) investigational therapy in advanced DKK1 high gastroesophageal adenocarcinoma (GEA): DisTinGuish Trial. J. ImmunoTher. Cancer 2022, 10 (Suppl. 2), A578. [Google Scholar] [CrossRef]
  100. Wall, J.A.; Klempner, S.J.; Arend, R.C. The anti-DKK1 antibody DKN-01 as an immunomodulatory combination partner for the treatment of cancer. Expert Opin. Investig. Drugs 2020, 29, 639–644. [Google Scholar] [CrossRef] [PubMed]
  101. Zhang, Y.; Liang, K.; Zhou, X.; Zhang, X.; Xu, H.; Dai, H.; Song, X.; Yang, X.; Liu, B.; Shi, T.; et al. Combination therapy of DKK1 inhibition and NKG2D chimeric antigen receptor T cells for the treatment of gastric cancer. Cancer Sci. 2023, 114, 2798–2809. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  102. Sui, Q.; Liu, D.; Jiang, W.; Tang, J.; Kong, L.; Han, K.; Liao, L.; Li, Y.; Ou, Q.; Xiao, B.; et al. Dickkopf 1 impairs the tumor response to PD-1 blockade by inactivating CD8+ T cells in deficient mismatch repair colorectal cancer. J. Immunother. Cancer 2021, 9, e001498, Erratum in J. Immunother. Cancer 2021, 9, 1. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  103. Haas, M.S.; Kagey, M.H.; Heath, H.; Schuerpf, F.; Rottman, J.B.; Newman, W. mDKN-01, a Novel Anti-DKK1 mAb, Enhances Innate Immune Responses in the Tumor Microenvironment. Mol. Cancer Res. 2021, 19, 717–725. [Google Scholar] [CrossRef] [PubMed]
  104. Mourtada, J.; Thibaudeau, C.; Wasylyk, B.; Jung, A.C. The Multifaceted Role of Human Dickkopf-3 (DKK-3) in Development, Immune Modulation and Cancer. Cells 2023, 13, 75. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  105. Ryan, D.P.; Murphy, J.; Mahalingam, D.; Strickler, J.; Stein, S.; Sirard, C.; Landau, S.; Bendell, J. PD-016: Current results of a phase I study of DKN-01 in combination with paclitaxel (P) in patients (pts) with advanced DKK1+ esophageal cancer (EC) or gastro-esophageal junction tumors (GEJ). Ann. Oncol. 2016, 27 (Suppl. 2), ii108. [Google Scholar] [CrossRef] [PubMed Central]
  106. Bhavanasi, D.; Speer, K.F.; Klein, P.S. CKAP4 is identified as a receptor for Dickkopf in cancer cells. J. Clin. Investig. 2016, 126, 2419–2421. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  107. Kikuchi, A.; Fumoto, K.; Kimura, H. The Dickkopf1-cytoskeleton-associated protein 4 axis creates a novel signalling pathway and may represent a molecular target for cancer therapy. Br. J. Pharmacol. 2017, 174, 4651–4665. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  108. Kikuchi, A.; Matsumoto, S.; Sada, R. Dickkopf signaling, beyond Wnt-mediated biology. Semin. Cell Dev. Biol. 2022, 125, 55–65. [Google Scholar] [CrossRef] [PubMed]
  109. Sada, R.; Kimura, H.; Fukata, Y.; Fukata, M.; Yamamoto, H.; Kikuchi, A. Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6. Sci. Signal. 2019, 12, eaat9519. [Google Scholar] [CrossRef] [PubMed]
  110. Al Shareef, Z.; Ershaid, M.N.A.; Mudhafar, R.; Soliman, S.S.M.; Kypta, R.M. Dickkopf-3: An Update on a Potential Regulator of the Tumor Microenvironment. Cancers 2022, 14, 5822. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  111. Iguchi, K.; Sada, R.; Matsumoto, S.; Kimura, H.; Zen, Y.; Akita, M.; Gon, H.; Fukumoto, T.; Kikuchi, A. DKK1-CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness. Cancer Sci. 2023, 114, 2063–2077. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  112. Shinno, N.; Kimura, H.; Sada, R.; Takiguchi, S.; Mori, M.; Fumoto, K.; Doki, Y.; Kikuchi, A. Activation of the Dickkopf1-CKAP4 pathway is associated with poor prognosis of esophageal cancer and anti-CKAP4 antibody may be a new therapeutic drug. Oncogene 2018, 37, 3471–3484. [Google Scholar] [CrossRef] [PubMed]
  113. Osugi, Y.; Fumoto, K.; Kikuchi, A. CKAP4 Regulates Cell Migration via the Interaction with and Recycling of Integrin. Mol. Cell Biol. 2019, 39, e00073-19. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  114. Kajiwara, C.; Fumoto, K.; Kimura, H.; Nojima, S.; Asano, K.; Odagiri, K.; Yamasaki, M.; Hikita, H.; Takehara, T.; Doki, Y.; et al. p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4. Cancer Res. 2018, 78, 6107–6120. [Google Scholar] [CrossRef] [PubMed]
  115. Li, S.X.; Li, J.; Dong, L.W.; Guo, Z.Y. Cytoskeleton-Associated Protein 4, a Promising Biomarker for Tumor Diagnosis and Therapy. Front. Mol. Biosci. 2021, 7, 552056. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
  116. Sada, R.; Yamamoto, H.; Matsumoto, S.; Harada, A.; Kikuchi, A. Newly developed humanized anti-CKAP4 antibody suppresses pancreatic cancer growth by inhibiting DKK1-CKAP4 signaling. Cancer Sci. 2024. Epub ahead of print. [Google Scholar] [CrossRef] [PubMed]
Diagnostics 15 00085 g001
Figure 1. The role of DKK1: (A) DKK1binding to LRP5/6 leads to β-catenin degradation, (B) tertiary complex of DKK1 with LRP5/6 and Kremen lead to its internalization; and (C) DKK1 binding to LRP5/6 can lead to JNK activation independently of β-catenin. Axin, axis inhibition protein; APC, adenomatous polyposis coli; GSK-3β, glycogen synthase kinase 3β; CK1α, casein kinase 1α; ROR/RYK, receptor-like tyrosine kinase; Dvl, Disheveled; JNK, Jun N-terminal kinase.
Figure 1. The role of DKK1: (A) DKK1binding to LRP5/6 leads to β-catenin degradation, (B) tertiary complex of DKK1 with LRP5/6 and Kremen lead to its internalization; and (C) DKK1 binding to LRP5/6 can lead to JNK activation independently of β-catenin. Axin, axis inhibition protein; APC, adenomatous polyposis coli; GSK-3β, glycogen synthase kinase 3β; CK1α, casein kinase 1α; ROR/RYK, receptor-like tyrosine kinase; Dvl, Disheveled; JNK, Jun N-terminal kinase.
Diagnostics 15 00085 g001
Diagnostics 15 00085 g002
Figure 2. DKK1-CKAP4 axis. The presence of both DKK1 and CKAP4 leads to activation of Akt-mediated oncogenic molecular pathways. CKAP4, cytoskeleton-associated protein 4; PI3K, phosphoinositide 3-kinase (consisted of p85 and p110 subunits); PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; Akt protein kinase B; FOXM1, forkhead box M1.
Figure 2. DKK1-CKAP4 axis. The presence of both DKK1 and CKAP4 leads to activation of Akt-mediated oncogenic molecular pathways. CKAP4, cytoskeleton-associated protein 4; PI3K, phosphoinositide 3-kinase (consisted of p85 and p110 subunits); PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; Akt protein kinase B; FOXM1, forkhead box M1.
Diagnostics 15 00085 g002
Table 1. Role of DKK1 in cancer.
Table 1. Role of DKK1 in cancer.
Type of TumorDKK1 RoleDownstream MechanismReceptor That Mediates the DKK1 FunctionStudies
Colorectal cancer1. Tumor suppressor
2. Oncogene		1. Inhibition of expression of VEGF [10], inhibition of Wnt/β-catenin pathway [11]
2. Independent of Wnt [12]		1. LRP5/6 [11], not defined [10]
2. Not defined		1. Liu et al. [10],
Qi et al. [11]
2. Aguilera et al. [12],
Gurluler et al. [13]
HCCOncogeneWnt/β-catenin pathway [14]Not definedYu et al. [14],
Yang et al. [15],
Tung et al. [16],
Tao et al. [17]
Gastric cancerOncogeneNot definedNot definedLee et al. [18],
Liu et al. [19]
Ovarian cancerOncogeneOverexpression/activation of P-JNK1 [20]Possibly Fzd [20]Klotz et al. [21],
Shizhuo et al. [22],
Wang et al. [20]
Breast cancerOncogeneWnt/beta-catenin pathway [23]Not definedZhou et al. [24],
Xu et al. [23]
Lung cancerOncogeneNot definedNot definedDong et al. [25],
Yamabuki et al. [26],
Sheng et al. [27]
Esophageal carcinomaOncogenePhosphorylation of AktNot definedLyros et al. [4],
Yamabuki et al. [26],
Begenik et al. [28],
Peng et al. [29],
Makino et al. [30]
Kimura et al. [31]
Urothelial cancerOncogeneNot definedNot definedShen et al. [32],
Sun et al. [33]
Pancreatic cancerOncogeneAKT/MEK-ERK pathway, overexpression of FOXM1CKAP4Kimura et al. [31],
Takahashi et al. [34],
Liu et al. [35]
Table 2. Studies of DKN-01 in EAC.
Table 2. Studies of DKN-01 in EAC.
StudyPhasenTreatment LineTreatment Arm2nd Treatment ArmOS/PFS
NCT02013154 [87,105]1b22≥2nd lineDKN-01 + paclitaxel [105]-28.9/17.7 (weeks)
63≥2nd lineDKN-01 + pembrolizumab [87]-20.4/6 (weeks)
DISTINGUISH-PART A [98]2251st lineDKN-01 + tislelizumab + CAPOX-19.5/11.3 (months)
DISTINGUISH-PART B [99]2522nd lineDKN-01 + tislelizumab-1.4/-(months)
DISTINGUISH-PART C [NCT04363801]2160 (1:1)1st lineDKN-01 + tislelizumab + CAPOX or FOLFOX6Tislelizumab + CAPOX or FOLFOX6Ongoing
NCT041667212Recruiting≥2nd lineDKN-01 + atezolizumab-Ongoing
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Despotidis, M.; Lyros, O.; Driva, T.S.; Sarantis, P.; Kapetanakis, E.I.; Mylonakis, A.; Mamilos, A.; Sakellariou, S.; Schizas, D. DKK1 and Its Receptors in Esophageal Adenocarcinoma: A Promising Molecular Target. Diagnostics 2025, 15, 85. https://doi.org/10.3390/diagnostics15010085

AMA Style

Despotidis M, Lyros O, Driva TS, Sarantis P, Kapetanakis EI, Mylonakis A, Mamilos A, Sakellariou S, Schizas D. DKK1 and Its Receptors in Esophageal Adenocarcinoma: A Promising Molecular Target. Diagnostics. 2025; 15(1):85. https://doi.org/10.3390/diagnostics15010085

Chicago/Turabian Style

Despotidis, Markos, Orestis Lyros, Tatiana S. Driva, Panagiotis Sarantis, Emmanouil I. Kapetanakis, Adam Mylonakis, Andreas Mamilos, Stratigoula Sakellariou, and Dimitrios Schizas. 2025. "DKK1 and Its Receptors in Esophageal Adenocarcinoma: A Promising Molecular Target" Diagnostics 15, no. 1: 85. https://doi.org/10.3390/diagnostics15010085

APA Style

Despotidis, M., Lyros, O., Driva, T. S., Sarantis, P., Kapetanakis, E. I., Mylonakis, A., Mamilos, A., Sakellariou, S., & Schizas, D. (2025). DKK1 and Its Receptors in Esophageal Adenocarcinoma: A Promising Molecular Target. Diagnostics, 15(1), 85. https://doi.org/10.3390/diagnostics15010085

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop