Patient-derived xenograft: a developing tool for screening biomarkers and potential therapeutic targets for human esophageal cancers

Methods for establishing EC PDX models and characteristics of EC-PDX

The engraftment rates of PDX

The engraftment rates of subcutaneous PDX for EC vary from 13.3% to 55.5%, as reported in several studies listed in Table 1. In Table 2, the success rates of PDX for other tumors including neuroblastoma, osteosarcoma, osteosarcoma and so on are listed, which vary from 24% to 100%. The take rate of orthotopic PDX for EC is claimed as 100%, however, the extremely limited sample size (only one case) used in this study may strongly affect the estimation of the take rate [15]. Because of the anatomical location of the esophagus, the establishment of orthotopic model of EC requires advanced surgical techniques, and hardly achieves simplicity or reproducibility [16, 17]. Therefore, orthotopic PDX models for EC are rarely employed. Both resected tumor tissues and endoscopic biopsies are suitable for the engraftment. Resected tumor tissues are often obtained during surgery, while biopsy specimens are obtained during endoscopic examination for pathological confirmation. Tumor tissues or biopsy specimens are then fragmented and these tissue fragments will be directly implanted or blended with Matrigel before implanting into immunocompromised mice for tumor growth and expansion. Esophageal tumor cell populations isolated from ESCC tissues have also been implanted to establish PDX model [18].

Table 1. A summary of PDX models for esophageal cancer.

Histology	Tissue type	Implantation method	Mouse strain	Xenograft success rate (%)	Refs.
ESCC	Resected	SC	SCID mice	37/96 (38.5)	[19]
ESCC/EAC	Resected	SC	NSG mice	ESCC 4/12 (25) EAC 13/49 (33)	[20]
ESCC	Resected	SC	SCID mice	14/26 (53.6)	[21]
ESCC	Biopsy	SC	NOD-SCID mice	25/188 (13.3)	[22]
ESCC / EAC	Biopsy	SC	NOD-SCID/NSG mice	ESCC 5/16(31) EAC 8/54(33)	[27]
GEJ adenocarcinoma	Biopsy	Ort	SCID mice	1/1 (100)	[15]
GEJ/ESCC/EAC	Resected/biopsy	IM/SC	SCID/NOD-SCID/NSG mice	IM 13/18 (72) SC 1/6 (16)	[33]
ESCC	Resected	SC	Athymic nude mice	61/110 (55.5)	[36]
ESCC	Resected	SC	NOD-SCID mice	23/54 (42.6)	[42]
GEJ/ ESCC/EAC	Resected	SC	NOD-SCID mice	21/55 (38)	[43]
ESCC	Resected	SC	SICD mice	25/54(46.3)	[39]
ESCC: esophageal squamous cell carcinoma; GEJ: gastroesophageal junction; EAC: esophageal adenocarcinoma; SC: Subcutaneous; Ort: orthotopic; IM: Intramuscular; SCID: C.B17-Prkdcscid; NOD-SCID: NOD.C.B17-Prkdcscid; NSG: NOD.Cg-PrkdcscidIl2rgtm1Wjl.

Table 2. The success rate of PDX for other tumor types.

Tumor types	Methods	Recipient	Success rates%	Refs.
neuroblastoma	Ort	NSG/ athymic nude mice	24	[44]
osteosarcoma	Ort	NSG/ athymic nude mice	48	[44]
rhabdomyosarcoma	Ort	NSG/ athymic nude mice	65	[44]
retinoblastoma	Ort	SCID/athymic nude mice	70	[44]
Wilms tumour	Ort	NSG/ athymic nude mice	78	[44]
desmoplastic small round-cell tumour	Ort	NSG/ athymic nude mice	22	[44]
Ewing sarcoma	Ort	NSG/ athymic nude mice	29	[44]
high-grade sarcoma	Ort	NSG/ athymic nude mice	83	[44]
Colorectal cancer	SC	athymic nude mice	52	[45]
Prostate cancer	SC	SCID/NSG/ C57BL/6 pfp/rag2 mice	100-66	[46]
SC: Subcutaneous; Ort: orthotopic; SCID: C.B17-Prkdcscid; NOD-SCID: NOD.C.B17-Prkdcscid; NSG: NOD.Cg-PrkdcscidIl2rgtm1Wjl.

Tumor tissues or biopsy specimens from EC patients are termed P0 (Passage zero); established PDX models are termed passage 1 (P1); when P1 tumors reached 500~1500 mm³, fresh tumor fragments are harvested from mice and then subsequently re-implanted into other mice (P2, P3, and so on) [19–22]. In general, PDX models undergoing more than 3 passages (P3) are applicable for drug test experiments. If tumor growth was not detected for at least 6 months or the mass was caused by non-epithelial cell proliferation, the engraftment would be considered as a failure.

The recipients of PDXs

Immunodeficient mice suitable to receive human tumor tissues include athymic nude mice, C.B17-Prkdc^scid (SCID) mice, non-obese diabetic.C.B17-Prkdc^scid (NOD-SCID) mice, NOD.Cg-Prkdc^scidIl2rg^tm1Wjl (NSG) mice and NODShi.Cg-Prkdc^scid Il2rg^tm1Sug (NOG/SCID) (Table 1). A spontaneous mutation of Foxn1 gene in athymic nude mice results in the deteriorated or absent thymus [23]. They are also characterized by the defective differentiation and proliferation of thymic epithelial cells (TECs) and progenitors of T-lymphocytes [23]. However, an intact innate immune system remains and NK cell activity is high, thus engraftment is limited for most primary solid human tumors and impossible for human normal or malignant hematopoietic cells [24]. SCID mice lack both functional T and B lymphocytes because of a Prkdc gene deficiency. The concept of SCID now expands to all severely immunodeficient strains of mice, such as those with Recombination activating gene-1/2 mutation (Rag-1^null/Rag-2^null). The engraftment takes rates of human tumor cells (including neuroblastoma, colon cancer, and breast cancer cell line) are higher in SCID mice than nude mice [25]. However, moderate NK cell activity remaining in SCID mice restricts the growth of human hematopoietic cells and PDX tumors after implantation. NOD-SCID mice are cultivated by crossbreeding NOD mice and SCID mice. These immunocompromised mice display defective innate immunity, including the dampened activity of NK cell and macrophages, abnormal dendritic cell development and function, and a lack of complement activation [26]. Therefore, NOD-SICD mice are more suitable for the engraftment of human solid tumors and hematopoietic cells that fail in SCID mice. IL-2 receptor subunit gamma (IL-2Rγ) is indispensable for high-affinity signaling for the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. A lack of IL-2Rγ cripples both the adaptive and innate immune system. NSG mice combine the characters of NOD-SICD mice and IL-2Rγ^null mice, and are highly receptive to engraftment of human primary tumors. Nevertheless, no significant improvement in primary EC engraftment has been found using NSG mice compared with NOD-SCID mice [27]. Similarly to NSG mice, NOG mice also lack T and B lymphocytes and NK cells and are compatible with human cells and tissues [28]. The engraftment rate of human hematopoietic cells in NOG mice are significantly elevated when compared with NOD-SCID mice [29]. However, there is no evidence indicating NOG mice are superior recipients for EC-PDX.

Most studies that establish a EC-PDX model used animals aged 6-8 weeks for engraftment of patient-derived xenografts, aging mice might not be suitable for xenografts implantation. The reasons may include: (1) The activity of T cell in athymic nude mice tends to increase with the age. Therefore, engraftment rate of tumor cells or tissues could be enhanced in younger mice (5-10 weeks) (reviewed by Szadvari et al [23]); (2) In some aging mice, such as SCID mice, spontaneous thymic and non-thymic tumors may develop and seriously affect their survival, even they are maintained in an SPF, barrier-protected environment [30]; (3) the life spans of immunodeficient mice vary across different species. The median life span of NOD-SCID mice has been reported as 37 weeks, while that of NSG mice was 89 weeks (range, 59–95 weeks) [26, 31]. (4) Inflammatory conditions are also present in aging NSG female mice and contribute to morbidity and mortality in these mice [32].

The engraftment methods

Currently, subcutaneous, orthotopic, and intramuscular implanting are three methods employed by researchers in the establishment of PDX models for EC (Table 1). Subcutaneous engraftment is a well-established technique employed by most researchers in establishing PDX models. Both resected tumor tissues or biopsy derived from human ESCC or EAC could be engrafted subcutaneously into immunodeficient mice. Orthotopic implantation of human primary EC tissues is scarcely reported. Veeranki et al [15] transabdominally implanted a biopsy sample of EAC at the distal esophagus/gastroesophageal junction to mimic tumor growth patterns in patients. The orthotopic mouse model closely mimics tumor growth patterns seen in patients and recapitulated the response to radiation treatment in patients with EAC [15]. A study showed that intramuscular engraftment might improve the success rate of esophageal PDX establishment (intramuscular vs subcutaneous, 72% vs 16%) [33]. They attributed the improvement to a more abundant blood supply in the muscles than cutaneous tissue. This novel method in tumor tissue engraftment may optimize the process of testing therapeutic drugs for EC. However, lymphomatous transformation occurred in some xenografts when using the intramuscular method [33]. Intramuscular engraftment has also been used in establishing xenograft models for canine osteosarcoma and human ovarian tissues [34, 35]. The feasibility of this engraftment approach should be further validated by more studies. The procedures in establishing PDX models of EC are summarized in Figure 1.

Figure 1. The procedures in establishing patient-derived xenograft models of esophageal cancer. Tumor tissues or biopsy are obtained from patients with EC during surgery or endoscopic examination. These tumor tissues and biopsy are termed P0 and are then fragmented before implantation. In some condition, cell populations are isolated from tumor tissues for PDX model establishment. Fragmented samples or primary tumor cells are then implanted into immunocompromised mice (termed P1), either subcutaneously or orthotopically. When P1 tumors reached 500~1500 mm3, fresh tumor fragments are harvested from mice and then subsequently re-implanted into other mice for expansion (P2, P3, and so on).

Characteristics of EC-PDX

Distinguishing features of EC-PDX models support them become useful tools in translational cancer research. Firstly, the morphology and histology in EC-PDX remained consistent when compared that of the corresponding primary tumor tissues [22]. Through 3-4 passages, the degree of differentiation in tumor xenografts varied slightly [22]. Importantly, drug sensitivity, including paclitaxel and cisplatin, in PDX models correlates well with the clinical response in corresponding patients [22]. Thus, EC-PDX model provided a realistic model for drug sensitivity selection for EC patients [22, 36, 37]. Secondly, EC-PDXs are able to mimic the current clinical genetic setting of EC, including mutations in PIK3CA, EGFR, K-Ras, B-Raf and HER2 amplification [19]. These models may support further investigation of the effect of driver gene mutation on treatment response. For instance, the efficacy of Trastuzumab has been developed for the treatment of HER2 positive breast cancer [38]. Likewise, Trastuzumab caused tumor regression in HER2 positive EC-PDX models [39]. However, when PIK3CA mutation was present in the models, Trastuzumab lost the ability to suppress tumor growth, which suggest PIK3CA mutation may be a mechanism of Trastuzumab resistance [39]. Clinical response to chemotherapy using 5-FU and cisplatin was also compromised in EC-PDX models with PIK3CA mutation [19]. Additionally, cancer associated fibroblasts (CAFs) constitute the majority of the tumor microenvironment (TME) [8]. CAFs may promote tumor growth through their mechanical contributions to the stroma and cytokines secretion [40]. Unlike in cell line xenograft, patient-derived CAFs are preserved well in PDX models and contribute to the therapy resistance of EAC [41]. Therefore, PDX models are superior in studying the interaction between EC and TME.

Conclusions

PDX models of EC are increasingly utilized for studying tumor biology, investigating genetic heterogeneity, and screening predictive biomarkers and therapeutic targets (Table 3). Indeed, investigators have tested various drugs or radiation therapy on mice bearing PDX and screened predictive biomarkers/ therapeutic targets that may guide for EC therapy in patients (Figure 2).

Table 3. Agents and their targets tested in PDX models of esophageal cancer.

Agent	Target	Histology	Administration method	Mouse strain	Reference
Gimatecan	Topoisomerase I	ESCC	Oral gavage	NOD-SCID mice	[61]
HCPT	Topoisomerase I	ESCC	Paraneoplastic injection	SCID mice	[59]
Cetuximab	EGFR	ESCC	Intraperitoneal injection	Athymic nude mice	[36]
Theliatinib	EGFR	ESCC	Oral gavage	NOD-SCID mice	[42]
Trastuzumab	HER2	EAC	Intraperitoneal injection	NSG mice	[70]
Trastuzumab/ pertuzumab	HER2/HER3	EAC	Intraperitoneal injection	NSG mice	[160]
Afatinib dasatinib	EGFR /Src family kinase	ESCC	Oral gavage	NOD-SCID mice	[73]
Afatinib/AMG 337	HER2/MET	EG	-	-	[74]
Lapatinib	EGFR/HER2	ESCC	Oral gavage	Athymic nude mice	[75]
APIO-EE-9	Aurora A and B	ESCC	-	SCID mice	[82]
SHR6390	CDK4/6	ESCC	Oral gavage	NOD-SCID mice	[90]
Palbociclib	CDK4/6	ESCC	Oral gavage	BALB/c nude mice	[37]
BAY1143572	CDK9	EAC	Intraperitoneal injection	Athymic nude mice	[92]
AdSOCS1	SOCS1	ESCC	Intratumoral injection	NOD-SCID	[98]
Metformin	JAK/STAT3	ESCC	-	SCID mice	[99]
Stattic	STAT3	ESCC	Intraperitoneal injection	SCID mice	[100]
Purpurogallin	MEK1/2	ESCC	Oral gavage	SCID mice	[107]
Ethyl gallate	ERK1/2	ESCC	Oral gavage	SCID mcie	[111]
Sulforaphene	MSK2	ESCC	Intraperitoneal injection	SCID mice	[114]
Gossypetin	MKK3/6	ESCC	Oral gavage	SCID mice	[115]
Anti-Glypican-1 mAb	Glypican-1	ESCC	Intraperitoneal injection	NOG/SCID mice	[119]
5E1 LDE225	SHH SMO	EAC	Intraperitoneal injection Oral gavage	NOD-SCID/NSG mice	[124]
CYH33	PI3Kα	ESCC	Oral gavage	BALB/c nude mice	[132]
Oridonin	Akt	ESCC	Oral gavage	SCID mice	[133]
Xanthohumol	Akt	ESCC	Oral gavage	SCID mice	[134]
Scutellarin	Akt1/2	ESCC	Oral gavage	SCID mice	[135]
DC101	VEGFR2	EAC	Intraperitoneal injection	Athymic nude mice	[144]
Ganetespib	HSP90	ESCC	Intraperitoneal injection	NSG mice	[148]
DAPT	Notch signaling	EAC	Intraperitoneal injection	NSG	[152]
PPMP	Tubulin	ESCC	Intraperitoneal injection	SCID mice	[156]
Antisense oligonucleotides	LncRNA AGPG	ESCC	Intratumoral injection	Athymic nude mice	[159]
HCPT: (S)-10-Hydroxycamptothecin; EGFR: epidermal growth factor receptor; HER2: erb-b2 receptor tyrosine kinase 2; HER3: erb-b2 receptor tyrosine kinase 3; MET: MET proto-oncogene, receptor tyrosine kinase; CDK4/6/9:cyclin dependent kinase 4/6/9; SOCS1:suppressor of cytokine signaling 1; JAK: Janus kinase; STAT3:signal transducer and activator of transcription 3; MEK1/2:mitogen-activated protein kinase kinase 1/2; ERK1/2: extracellular signal-regulated kinase 1/2; MSK2:ribosomal protein S6 kinase A4; MKK3/6:mitogen-activated protein kinase kinase 3/6; SHH: sonic hedgehog; SMO: smoothened, frizzled class receptor; PI3Kα:phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; Akt: serine/threonine kinase 1; VEGFR2: vascular endothelial growth factor receptor 2; HSP90: heat shock protein 90; EAC: esophageal adenocarcinoma; ESCC: esophageal squamous cell carcinoma; EG: esophagogastric cancer; SCID: C.B17-Prkdcscid; NOD-SCID: NOD.C.B17-Prkdcscid; NOG/SCID: NODShi.Cg-Prkdcscid Il2rgtm1Sug; NSG: NOD.Cg-PrkdcscidIl2rgtm1Wjl.

Figure 2. The application of patient-derived xenograft (PDX) in screening predictive biomarkers and therapeutic targets for esophageal cancer therapy. Esophageal cancer tissues are obtained from patients and implanted into immunodeficient mice for PDX models establishment. With the PDX models, the treatment response of chemotherapeutic drugs, radiotherapeutic methods or targeted drugs are tested on these tumor xenografts. Subsequently, genome-wide sequencing techniques and expressional analysis are carried out to screen genes with differential expression, which are related to various therapeutic methods. Through bioinformatic analysis, potential biomarkers are selected from differentially expressed genes. Finally, clinical trials are designed and performed to validate the feasibility of these biomarkers.

However, there are still several problems that need to be solved in the establishment and usage of EC-PDX:

1. The engraftment rates of EC-PDX remain relatively low with the current methods, and only a minority of tumor tissues derived from patients can be successfully engrafted. As a result, there is a high cost in establishing successful PDX models. To solve this issue, novel immunodeficient animals are needed, such as gene-modified rats and hamsters [161–163];

2. Although subcutaneous engraftment is commonly employed by most researchers [164], subcutaneous models less accurately reflect tumor progression compared with orthotopic methods and hinder the investigation of tumor metastasis, angiogenesis and tumor microenvironment in EC. The difficulties in establishing and examining orthotopic PDX models have become the roadblocks for the popularization of this tool;

3. A replacement of human stromal cells by mouse stroma occurs in the initial stage of PDX establishment [20], which blocks the study of the interaction between EC cells and stromal cells due to the loss of human stromal cells in PDX;

4. A lack of a functional immune system also prevents the analysis of immunotherapeutic approaches to EC therapy.

Although the drawbacks exist in the current EC-PDX models, the development of novel immunodeficient animals may help accelerate their usage in a preclinical study. For instance, tumor cells in immunodeficient Syrian hamster can communicate with host fibroblasts, which may provide growth factors to keep human cancer and stromal cells survive longer [163]. Moreover, humanized animal models with reconstituted human immune cells will be more meaningful, which allow the investigation of the interaction between cancer cells and various human immune cells.

Author Contributions

TL, JM, and YW: manuscript concept and design. TL: manuscript writing. XX, JM, LCD, and YW: manuscript revising.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Funding

This project is supported by the National Key R&D Program of China (NO. 2016YFE0200800), Natural Science Foundation of Henan Province (No. 202300410259), Postdoctoral Research Startup Project in Henan Province (No.202001043), the Nature Sciences Foundation of China (NO. 81771776 and U1704282) and The MRC (NO. MR/M015696/1).

References

• 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68:394–424. https://doi.org/10.3322/caac.21492 [PubMed]
• 2. Malhotra GK, Yanala U, Ravipati A, Follet M, Vijayakumar M, Are C. Global trends in esophageal cancer. J Surg Oncol. 2017; 115:564–79. https://doi.org/10.1002/jso.24592 [PubMed]
• 3. Liu K, Zhao T, Wang J, Chen Y, Zhang R, Lan X, Que J. Etiology, cancer stem cells and potential diagnostic biomarkers for esophageal cancer. Cancer Lett. 2019; 458:21–28. https://doi.org/10.1016/j.canlet.2019.05.018 [PubMed]
• 4. Abnet CC, Arnold M, Wei WQ. Epidemiology of Esophageal Squamous Cell Carcinoma. Gastroenterology. 2018; 154:360–73. https://doi.org/10.1053/j.gastro.2017.08.023 [PubMed]
• 5. Taccioli C, Chen H, Jiang Y, Liu XP, Huang K, Smalley KJ, Farber JL, Croce CM, Fong LY. Dietary zinc deficiency fuels esophageal cancer development by inducing a distinct inflammatory signature. Oncogene. 2012; 31:4550–58. https://doi.org/10.1038/onc.2011.592 [PubMed]
• 6. Chen Y, Tong Y, Yang C, Gan Y, Sun H, Bi H, Cao S, Yin X, Lu Z. Consumption of hot beverages and foods and the risk of esophageal cancer: a meta-analysis of observational studies. BMC Cancer. 2015; 15:449. https://doi.org/10.1186/s12885-015-1185-1 [PubMed]
• 7. Wang RH. From reflux esophagitis to Barrett’s esophagus and esophageal adenocarcinoma. World J Gastroenterol. 2015; 21:5210–19. https://doi.org/10.3748/wjg.v21.i17.5210 [PubMed]
• 8. Lin EW, Karakasheva TA, Hicks PD, Bass AJ, Rustgi AK. The tumor microenvironment in esophageal cancer. Oncogene. 2016; 35:5337–49. https://doi.org/10.1038/onc.2016.34 [PubMed]
• 9. Arnold M, Soerjomataram I, Ferlay J, Forman D. Global incidence of oesophageal cancer by histological subtype in 2012. Gut. 2015; 64:381–87. https://doi.org/10.1136/gutjnl-2014-308124 [PubMed]
• 10. Gupta B, Kumar N. Worldwide incidence, mortality and time trends for cancer of the oesophagus. Eur J Cancer Prev. 2017; 26:107–18. https://doi.org/10.1097/CEJ.0000000000000249 [PubMed]
• 11. Domper Arnal MJ, Ferrández Arenas Á, Lanas Arbeloa Á. Esophageal cancer: Risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol. 2015; 21:7933–43. https://doi.org/10.3748/wjg.v21.i26.7933 [PubMed]
• 12. Huang FL, Yu SJ. Esophageal cancer: Risk factors, genetic association, and treatment. Asian J Surg. 2018; 41:210–15. https://doi.org/10.1016/j.asjsur.2016.10.005 [PubMed]
• 13. Madhavan A, Kamarajah SK, Navidi M, Wahed S, Immanuel A, Hayes N, Griffin SM, Phillips AW. The impact of age on patients undergoing transthoracic esophagectomy for cancer. Dis Esophagus. 2021; 34:doaa056. https://doi.org/10.1093/dote/doaa056 [PubMed]
• 14. Zeng Y, Liang W, Liu J, He J, Ng CS, Liu CC, Petersen RH, Rocco G, D’Amico T, Brunelli A, Chen H, Zhi X, Dong X, et al, and written on behalf of the AME Thoracic Surgery Collaborative Group. Esophageal cancer in elderly patients: a population-based study. J Thorac Dis. 2018; 10:448–57. https://doi.org/10.21037/jtd.2018.01.89 [PubMed]
• 15. Veeranki OL, Tong Z, Mejia A, Verma A, Katkhuda R, Bassett R, Kim TB, Wang J, Lang W, Mino B, Solis L, Kingsley C, Norton W, et al. A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries. Dis Model Mech. 2019; 12:dmm041004. https://doi.org/10.1242/dmm.041004 [PubMed]
• 16. Hori T, Yamashita Y, Ohira M, Matsumura Y, Muguruma K, Hirakawa K. A novel orthotopic implantation model of human esophageal carcinoma in nude rats: CD44H mediates cancer cell invasion in vitro and in vivo. Int J Cancer. 2001; 92:489–96. https://doi.org/10.1002/ijc.1234 [PubMed]
• 17. Ohara T, Takaoka M, Sakurama K, Nagaishi K, Takeda H, Shirakawa Y, Yamatsuji T, Nagasaka T, Matsuoka J, Tanaka N, Naomoto Y. The establishment of a new mouse model with orthotopic esophageal cancer showing the esophageal stricture. Cancer Lett. 2010; 293:207–12. https://doi.org/10.1016/j.canlet.2010.01.017 [PubMed]
• 18. Liu A, Zhu J, Wu G, Cao L, Tan Z, Zhang S, Jiang L, Wu J, Li M, Song L, Li J. Antagonizing miR-455-3p inhibits chemoresistance and aggressiveness in esophageal squamous cell carcinoma. Mol Cancer. 2017; 16:106. https://doi.org/10.1186/s12943-017-0669-9 [PubMed]
• 19. Zhang J, Jiang D, Li X, Lv J, Xie L, Zheng L, Gavine PR, Hu Q, Shi Y, Tan L, Ge D, Xu S, Li L, et al. Establishment and characterization of esophageal squamous cell carcinoma patient-derived xenograft mouse models for preclinical drug discovery. Lab Invest. 2014; 94:917–26. https://doi.org/10.1038/labinvest.2014.77 [PubMed]
• 20. Damhofer H, Ebbing EA, Steins A, Welling L, Tol JA, Krishnadath KK, van Leusden T, van de Vijver MJ, Besselink MG, Busch OR, van Berge Henegouwen MI, van Delden O, Meijer SL, et al. Establishment of patient-derived xenograft models and cell lines for malignancies of the upper gastrointestinal tract. J Transl Med. 2015; 13:115. https://doi.org/10.1186/s12967-015-0469-1 [PubMed]
• 21. Jiang Y, Wu Q, Yang X, Zhao J, Jin Y, Li K, Ma Y, Chen X, Tian F, Zhao S, Xu J, Lu J, Yin X, et al. A method for establishing a patient-derived xenograft model to explore new therapeutic strategies for esophageal squamous cell carcinoma. Oncol Rep. 2016; 35:785–92. https://doi.org/10.3892/or.2015.4459 [PubMed]
• 22. Zou J, Liu Y, Wang J, Liu Z, Lu Z, Chen Z, Li Z, Dong B, Huang W, Li Y, Gao J, Shen L. Establishment and genomic characterizations of patient-derived esophageal squamous cell carcinoma xenograft models using biopsies for treatment optimization. J Transl Med. 2018; 16:15. https://doi.org/10.1186/s12967-018-1379-9 [PubMed]
• 23. Szadvari I, Krizanova O, Babula P. Athymic nude mice as an experimental model for cancer treatment. Physiol Res. 2016 (Suppl 4); 65:S441–53. https://doi.org/10.33549/physiolres.933526 [PubMed]
• 24. Budzynski W, Radzikowski C. Cytotoxic cells in immunodeficient athymic mice. Immunopharmacol Immunotoxicol. 1994; 16:319–46. https://doi.org/10.3109/08923979409007097 [PubMed]
• 25. Taghian A, Budach W, Zietman A, Freeman J, Gioioso D, Ruka W, Suit HD. Quantitative comparison between the transplantability of human and murine tumors into the subcutaneous tissue of NCr/Sed-nu/nu nude and severe combined immunodeficient mice. Cancer Res. 1993; 53:5012–17. [PubMed]
• 26. Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, McKenna S, Mobraaten L, Rajan TV, Greiner DL. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol. 1995; 154:180–91. [PubMed]
• 27. Dodbiba L, Teichman J, Fleet A, Thai H, Sun B, Panchal D, Patel D, Tse A, Chen Z, Faluyi OO, Renouf DJ, Girgis H, Bandarchi B, et al. Primary esophageal and gastro-esophageal junction cancer xenograft models: clinicopathological features and engraftment. Lab Invest. 2013; 93:397–407. https://doi.org/10.1038/labinvest.2013.8 [PubMed]
• 28. Ito M, Kobayashi K, Nakahata T. NOD/Shi-scid IL2rgamma(null) (NOG) mice more appropriate for humanized mouse models. Curr Top Microbiol Immunol. 2008; 324:53–76. https://doi.org/10.1007/978-3-540-75647-7_3 [PubMed]
• 29. Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, Ueyama Y, Koyanagi Y, Sugamura K, Tsuji K, Heike T, Nakahata T. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002; 100:3175–82. https://doi.org/10.1182/blood-2001-12-0207 [PubMed]
• 30. Huang P, Westmoreland SV, Jain RK, Fukumura D. Spontaneous nonthymic tumors in SCID mice. Comp Med. 2011; 61:227–34. [PubMed]
• 31. Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, Kotb M, Gillies SD, King M, Mangada J, Greiner DL, Handgretinger R. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005; 174:6477–89. https://doi.org/10.4049/jimmunol.174.10.6477 [PubMed]
• 32. Santagostino SF, Arbona RJ, Nashat MA, White JR, Monette S. Pathology of Aging in NOD scid gamma Female Mice. Vet Pathol. 2017; 54:855–69. https://doi.org/10.1177/0300985817698210 [PubMed]
• 33. Read M, Liu D, Duong CP, Cullinane C, Murray WK, Fennell CM, Shortt J, Westerman D, Burton P, Clemons NJ, Phillips WA. Intramuscular Transplantation Improves Engraftment Rates for Esophageal Patient-Derived Tumor Xenografts. Ann Surg Oncol. 2016; 23:305–11. https://doi.org/10.1245/s10434-015-4425-3 [PubMed]
• 34. Coomer AR, Farese JP, Milner R, Taylor D, Salute ME, Rajon DA, Bova FJ, Siemann DW. Development of an intramuscular xenograft model of canine osteosarcoma in mice for evaluation of the effects of radiation therapy. Am J Vet Res. 2009; 70:127–33. https://doi.org/10.2460/ajvr.70.1.127 [PubMed]
• 35. Oktay K. Ovarian tissue cryopreservation and transplantation: preliminary findings and implications for cancer patients. Hum Reprod Update. 2001; 7:526–34. https://doi.org/10.1093/humupd/7.6.526 [PubMed]
• 36. Zhu H, Wang C, Wang J, Chen D, Deng J, Deng J, Fan J, Badakhshi H, Huang X, Zhang L, Cai J, Guo S, Qian W, et al. A subset of esophageal squamous cell carcinoma patient-derived xenografts respond to cetuximab, which is predicted by high EGFR expression and amplification. J Thorac Dis. 2018; 10:5328–38. https://doi.org/10.21037/jtd.2018.09.18 [PubMed]
• 37. Su D, Zhang D, Jin J, Ying L, Han M, Chen K, Li B, Wu J, Xie Z, Zhang F, Lin Y, Cheng G, Li JY, et al. Identification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma. Nat Commun. 2019; 10:5076. https://doi.org/10.1038/s41467-019-12846-7 [PubMed]
• 38. Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, Castro G Jr, Untch M, Smith I, Gianni L, Baselga J, Al-Sakaff N, Lauer S, et al, and Herceptin Adjuvant (HERA) Trial Study Team. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017; 389:1195–205. https://doi.org/10.1016/S0140-6736(16)32616-2 [PubMed]
• 39. Wu X, Zhang J, Zhen R, Lv J, Zheng L, Su X, Zhu G, Gavine PR, Xu S, Lu S, Hou J, Liu Y, Xu C, et al. Trastuzumab anti-tumor efficacy in patient-derived esophageal squamous cell carcinoma xenograft (PDECX) mouse models. J Transl Med. 2012; 10:180. https://doi.org/10.1186/1479-5876-10-180 [PubMed]
• 40. Karakasheva TA, Lin EW, Tang Q, Qiao E, Waldron TJ, Soni M, Klein-Szanto AJ, Sahu V, Basu D, Ohashi S, Baba K, Giaccone ZT, Walker SR, et al. IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment. Cancer Res. 2018; 78:4957–70. https://doi.org/10.1158/0008-5472.CAN-17-2268 [PubMed]
• 41. Ebbing EA, van der Zalm AP, Steins A, Creemers A, Hermsen S, Rentenaar R, Klein M, Waasdorp C, Hooijer GK, Meijer SL, Krishnadath KK, Punt CJ, van Berge Henegouwen MI, et al. Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma. Proc Natl Acad Sci USA. 2019; 116:2237–42. https://doi.org/10.1073/pnas.1820459116 [PubMed]
• 42. Ren Y, Zheng J, Fan S, Wang L, Cheng M, Shi D, Zhang W, Tang R, Yu Y, Jiao L, Ni J, Yang H, Cai H, et al. Anti-tumor efficacy of theliatinib in esophageal cancer patient-derived xenografts models with epidermal growth factor receptor (EGFR) overexpression and gene amplification. Oncotarget. 2017; 8:50832–44. https://doi.org/10.18632/oncotarget.17243 [PubMed]
• 43. Dodbiba L, Teichman J, Fleet A, Thai H, Starmans MH, Navab R, Chen Z, Girgis H, Eng L, Espin-Garcia O, Shen X, Bandarchi B, Schwock J, et al. Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers. PLoS One. 2015; 10:e0121872. https://doi.org/10.1371/journal.pone.0121872 [PubMed]
• 44. Stewart E, Federico SM, Chen X, Shelat AA, Bradley C, Gordon B, Karlstrom A, Twarog NR, Clay MR, Bahrami A, Freeman BB 3rd, Xu B, Zhou X, et al. Orthotopic patient-derived xenografts of paediatric solid tumours. Nature. 2017; 549:96–100. https://doi.org/10.1038/nature23647 [PubMed]
• 45. Prasetyanti PR, van Hooff SR, van Herwaarden T, de Vries N, Kalloe K, Rodermond H, van Leersum R, de Jong JH, Franitza M, Nürnberg P, Todaro M, Stassi G, Medema JP. Capturing colorectal cancer inter-tumor heterogeneity in patient-derived xenograft (PDX) models. Int J Cancer. 2019; 144:366–71. https://doi.org/10.1002/ijc.31767 [PubMed]
• 46. Lange T, Oh-Hohenhorst SJ, Joosse SA, Pantel K, Hahn O, Gosau T, Dyshlovoy SA, Wellbrock J, Feldhaus S, Maar H, Gehrcke R, Kluth M, Simon R, et al. Development and Characterization of a Spontaneously Metastatic Patient-Derived Xenograft Model of Human Prostate Cancer. Sci Rep. 2018; 8:17535. https://doi.org/10.1038/s41598-018-35695-8 [PubMed]
• 47. Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J, Simes J, and Australasian Gastro-Intestinal Trials Group. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol. 2007; 8:226–34. https://doi.org/10.1016/S1470-2045(07)70039-6 [PubMed]
• 48. Blencowe NS, McNair AG, Davis CR, Brookes ST, Blazeby JM. Standards of outcome reporting in surgical oncology: a case study in esophageal cancer. Ann Surg Oncol. 2012; 19:4012–18. https://doi.org/10.1245/s10434-012-2497-x [PubMed]
• 49. Geng J, Yuan X, Wei M, Wu J, Qin ZH. The diverse role of TIGAR in cellular homeostasis and cancer. Free Radic Res. 2018; 52:1240–49. https://doi.org/10.1080/10715762.2018.1489133 [PubMed]
• 50. GongSun X, Zhao Y, Jiang B, Xin Z, Shi M, Song L, Qin Q, Wang Q, Liu X. Inhibition of MUC1-C regulates metabolism by AKT pathway in esophageal squamous cell carcinoma. J Cell Physiol. 2019; 234:12019–28. https://doi.org/10.1002/jcp.27863 [PubMed]
• 51. Chu J, Niu X, Chang J, Shao M, Peng L, Xi Y, Lin A, Wang C, Cui Q, Luo Y, Fan W, Chen Y, Sun Y, et al. Metabolic remodeling by TIGAR overexpression is a therapeutic target in esophageal squamous-cell carcinoma. Theranostics. 2020; 10:3488–502. https://doi.org/10.7150/thno.41427 [PubMed]
• 52. Ross D, Siegel D. Functions of NQO1 in Cellular Protection and CoQ₁₀ Metabolism and its Potential Role as a Redox Sensitive Molecular Switch. Front Physiol. 2017; 8:595. https://doi.org/10.3389/fphys.2017.00595 [PubMed]
• 53. Mizumoto A, Ohashi S, Kamada M, Saito T, Nakai Y, Baba K, Hirohashi K, Mitani Y, Kikuchi O, Matsubara J, Yamada A, Takahashi T, Lee H, et al. Combination treatment with highly bioavailable curcumin and NQO1 inhibitor exhibits potent antitumor effects on esophageal squamous cell carcinoma. J Gastroenterol. 2019; 54:687–98. https://doi.org/10.1007/s00535-019-01549-x [PubMed]
• 54. Gilmour DS, Pflugfelder G, Wang JC, Lis JT. Topoisomerase I interacts with transcribed regions in Drosophila cells. Cell. 1986; 44:401–07. https://doi.org/10.1016/0092-8674(86)90461-7 [PubMed]
• 55. Li M, Liu Y. Topoisomerase I in Human Disease Pathogenesis and Treatments. Genomics Proteomics Bioinformatics. 2016; 14:166–71. https://doi.org/10.1016/j.gpb.2016.02.004 [PubMed]
• 56. Pourquier P, Pommier Y. Topoisomerase I-mediated DNA damage. Adv Cancer Res. 2001; 80:189–216. https://doi.org/10.1016/S0065-230X(01)80016-6 [PubMed]
• 57. Leppard JB, Champoux JJ. Human DNA topoisomerase I: relaxation, roles, and damage control. Chromosoma. 2005; 114:75–85. https://doi.org/10.1007/s00412-005-0345-5 [PubMed]
• 58. Hanagiri T, Ono K, Kuwata T, Takenaka M, Oka S, Chikaishi Y, Shigematsu Y, Nagata Y, Shimokawa H, Nakagawa M, Uramoto H, So T, Tanaka F. Evaluation of topoisomerase I/topoisomerase IIalpha status in esophageal cancer. J UOEH. 2011; 33:205–16. https://doi.org/10.7888/juoeh.33.205 [PubMed]
• 59. Song M, Yin S, Zhao R, Liu K, Kundu JK, Shim JH, Lee MH, Dong Z. (S)-10-Hydroxycamptothecin Inhibits Esophageal Squamous Cell Carcinoma Growth In Vitro and In Vivo Via Decreasing Topoisomerase I Enzyme Activity. Cancers (Basel). 2019; 11:1964. https://doi.org/10.3390/cancers11121964 [PubMed]
• 60. Pratesi G, Beretta GL, Zunino F. Gimatecan, a novel camptothecin with a promising preclinical profile. Anticancer Drugs. 2004; 15:545–52. https://doi.org/10.1097/01.cad.0000131687.08175.14 [PubMed]
• 61. Zou J, Li S, Chen Z, Lu Z, Gao J, Zou J, Lin X, Li Y, Zhang C, Shen L. A novel oral camptothecin analog, gimatecan, exhibits superior antitumor efficacy than irinotecan toward esophageal squamous cell carcinoma in vitro and in vivo. Cell Death Dis. 2018; 9:661. https://doi.org/10.1038/s41419-018-0700-0 [PubMed]
• 62. Wang Z. ErbB Receptors and Cancer. Methods Mol Biol. 2017; 1652:3–35. https://doi.org/10.1007/978-1-4939-7219-7_1 [PubMed]
• 63. Roskoski R Jr. Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharmacol Res. 2019; 139:395–411. https://doi.org/10.1016/j.phrs.2018.11.014 [PubMed]
• 64. Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014; 25:282–303. https://doi.org/10.1016/j.ccr.2014.02.025 [PubMed]
• 65. Zhang W, Zhu H, Liu X, Wang Q, Zhang X, He J, Sun K, Liu X, Zhou Z, Xu N, Xiao Z. Epidermal growth factor receptor is a prognosis predictor in patients with esophageal squamous cell carcinoma. Ann Thorac Surg. 2014; 98:513–19. https://doi.org/10.1016/j.athoracsur.2014.03.015 [PubMed]
• 66. Wang WJ, Wu MJ, Chang J, Xie P, Lu ZQ, Ren JL. Role of human epidermal growth factor receptor 2 as a prognostic factor for survival in esophageal carcinoma: evidence from 2872 subjects. Minerva Med. 2016; 107:328–41. [PubMed]
• 67. Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995; 1:1311–18. [PubMed]
• 68. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, et al, and ToGA Trial Investigators. 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; 376:687–97. https://doi.org/10.1016/S0140-6736(10)61121-X [PubMed]
• 69. Doi T, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, Shimizu C, Shimoi T, Kuboki Y, Matsubara N, Kitano A, Jikoh T, Lee C, et al. Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study. Lancet Oncol. 2017; 18:1512–22. https://doi.org/10.1016/S1470-2045(17)30604-6 [PubMed]
• 70. Ebbing EA, Medema JP, Damhofer H, Meijer SL, Krishnadath KK, van Berge Henegouwen MI, Bijlsma MF, van Laarhoven HW. ADAM10-mediated release of heregulin confers resistance to trastuzumab by activating HER3. Oncotarget. 2016; 7:10243–54. https://doi.org/10.18632/oncotarget.7200 [PubMed]
• 71. Oh IJ, Hur JY, Park CK, Kim YC, Kim SJ, Lee MK, Kim HJ, Lee KY, Lee JC, Choi CM. Clinical Activity of Pan-HER Inhibitors Against HER2-Mutant Lung Adenocarcinoma. Clin Lung Cancer. 2018; 19:e775–81. https://doi.org/10.1016/j.cllc.2018.05.018 [PubMed]
• 72. Duchnowska R, Loibl S, Jassem J. Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer. Cancer Treat Rev. 2018; 67:71–77. https://doi.org/10.1016/j.ctrv.2018.05.004 [PubMed]
• 73. Liu Z, Chen Z, Wang J, Zhang M, Li Z, Wang S, Dong B, Zhang C, Gao J, Shen L. Mouse avatar models of esophageal squamous cell carcinoma proved the potential for EGFR-TKI afatinib and uncovered Src family kinases involved in acquired resistance. J Hematol Oncol. 2018; 11:109. https://doi.org/10.1186/s13045-018-0651-z [PubMed]
• 74. Sanchez-Vega F, Hechtman JF, Castel P, Ku GY, Tuvy Y, Won H, Fong CJ, Bouvier N, Nanjangud GJ, Soong J, Vakiani E, Schattner M, Kelsen DP, et al. EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer. Cancer Discov. 2019; 9:199–209. https://doi.org/10.1158/2159-8290.CD-18-0598 [PubMed]
• 75. Hou W, Qin X, Zhu X, Fei M, Liu P, Liu L, Moon H, Zhang P, Greshock J, Bachman KE, Ye BC, Wang H, Zang CY. Lapatinib inhibits the growth of esophageal squamous cell carcinoma and synergistically interacts with 5-fluorouracil in patient-derived xenograft models. Oncol Rep. 2013; 30:707–14. https://doi.org/10.3892/or.2013.2500 [PubMed]
• 76. Huang Y, Li T, Ems-McClung SC, Walczak CE, Prigent C, Zhu X, Zhang X, Zheng Y. Aurora A activation in mitosis promoted by BuGZ. J Cell Biol. 2018; 217:107–16. https://doi.org/10.1083/jcb.201706103 [PubMed]
• 77. Goldenson B, Crispino JD. The aurora kinases in cell cycle and leukemia. Oncogene. 2015; 34:537–45. https://doi.org/10.1038/onc.2014.14 [PubMed]
• 78. Tong T, Zhong Y, Kong J, Dong L, Song Y, Fu M, Liu Z, Wang M, Guo L, Lu S, Wu M, Zhan Q. Overexpression of Aurora-A contributes to malignant development of human esophageal squamous cell carcinoma. Clin Cancer Res. 2004; 10:7304–10. https://doi.org/10.1158/1078-0432.CCR-04-0806 [PubMed]
• 79. Lin YS, Su LJ, Yu CT, Wong FH, Yeh HH, Chen SL, Wu JC, Lin WJ, Shiue YL, Liu HS, Hsu SL, Lai JM, Huang CY. Gene expression profiles of the aurora family kinases. Gene Expr. 2006; 13:15–26. https://doi.org/10.3727/000000006783991962 [PubMed]
• 80. Wang X, Lu N, Niu B, Chen X, Xie J, Cheng N. Overexpression of Aurora-A enhances invasion and matrix metalloproteinase-2 expression in esophageal squamous cell carcinoma cells. Mol Cancer Res. 2012; 10:588–96. https://doi.org/10.1158/1541-7786.MCR-11-0416 [PubMed]
• 81. Yu X, Liang Q, Liu W, Zhou L, Li W, Liu H. Deguelin, an Aurora B Kinase Inhibitor, Exhibits Potent Anti-Tumor Effect in Human Esophageal Squamous Cell Carcinoma. EBioMedicine. 2017; 26:100–11. https://doi.org/10.1016/j.ebiom.2017.10.030 [PubMed]
• 82. Jin G, Yao K, Guo Z, Zhao Z, Liu K, Liu F, Chen H, Gorja DR, Reddy K, Bode AM, Dong Z, Dong Z. APIO-EE-9 is a novel Aurora A and B antagonist that suppresses esophageal cancer growth in a PDX mouse model. Oncotarget. 2017; 8:53387–404. https://doi.org/10.18632/oncotarget.18508 [PubMed]
• 83. Klein ME, Kovatcheva M, Davis LE, Tap WD, Koff A. CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought. Cancer Cell. 2018; 34:9–20. https://doi.org/10.1016/j.ccell.2018.03.023 [PubMed]
• 84. Hamilton E, Infante JR. Targeting CDK4/6 in patients with cancer. Cancer Treat Rev. 2016; 45:129–38. https://doi.org/10.1016/j.ctrv.2016.03.002 [PubMed]
• 85. Pernas S, Tolaney SM, Winer EP, Goel S. CDK4/6 inhibition in breast cancer: current practice and future directions. Ther Adv Med Oncol. 2018; 10:1758835918786451. https://doi.org/10.1177/1758835918786451 [PubMed]
• 86. Li F, Xu Y, Liu B, Singh PK, Zhao W, Jin J, Han G, Scott AW, Dong X, Huo L, Ma L, Pizzi MP, Wang Y, et al. YAP1-Mediated CDK6 Activation Confers Radiation Resistance in Esophageal Cancer - Rationale for the Combination of YAP1 and CDK4/6 Inhibitors in Esophageal Cancer. Clin Cancer Res. 2019; 25:2264–77. https://doi.org/10.1158/1078-0432.CCR-18-1029 [PubMed]
• 87. Xu Y, Li X, Xu YF, Yang XM. Poorly Differentiated Esophageal Neuroendocrine Carcinoma Treated With the CDK4/6 Inhibitor, Palbociclib: A Case Report and Literature Review. Am J Ther. 2018; 25:e595–98. https://doi.org/10.1097/MJT.0000000000000610 [PubMed]
• 88. Doi T, Hewes B, Kakizume T, Tajima T, Ishikawa N, Yamada Y. Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors. Cancer Sci. 2018; 109:193–98. https://doi.org/10.1111/cas.13428 [PubMed]
• 89. Frankell AM, Jammula S, Li X, Contino G, Killcoyne S, Abbas S, Perner J, Bower L, Devonshire G, Ococks E, Grehan N, Mok J, O’Donovan M, et al, and Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium. The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic. Nat Genet. 2019; 51:506–16. https://doi.org/10.1038/s41588-018-0331-5 [PubMed]
• 90. Wang J, Li Q, Yuan J, Wang J, Chen Z, Liu Z, Li Z, Lai Y, Gao J, Shen L. CDK4/6 inhibitor-SHR6390 exerts potent antitumor activity in esophageal squamous cell carcinoma by inhibiting phosphorylated Rb and inducing G1 cell cycle arrest. J Transl Med. 2017; 15:127. https://doi.org/10.1186/s12967-017-1231-7 [PubMed]
• 91. Tong Z, Chatterjee D, Deng D, Veeranki O, Mejia A, Ajani JA, Hofstetter W, Lin S, Guha S, Kopetz S, Krishnan S, Maru D. Antitumor effects of cyclin dependent kinase 9 inhibition in esophageal adenocarcinoma. Oncotarget. 2017; 8:28696–710. https://doi.org/10.18632/oncotarget.15645 [PubMed]
• 92. Veeranki OL, Tong Z, Dokey R, Mejia A, Zhang J, Qiao Y, Singh PK, Katkhuda R, Mino B, Tailor R, Canales JR, Bassett R, Ajani J, et al. Targeting cyclin-dependent kinase 9 by a novel inhibitor enhances radiosensitization and identifies Axl as a novel downstream target in esophageal adenocarcinoma. Oncotarget. 2019; 10:4703–18. https://doi.org/10.18632/oncotarget.27095 [PubMed]
• 93. You Z, Xu D, Ji J, Guo W, Zhu W, He J. JAK/STAT signal pathway activation promotes progression and survival of human oesophageal squamous cell carcinoma. Clin Transl Oncol. 2012; 14:143–49. https://doi.org/10.1007/s12094-012-0774-6 [PubMed]
• 94. Andl CD, Mizushima T, Oyama K, Bowser M, Nakagawa H, Rustgi AK. EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes. Am J Physiol Gastrointest Liver Physiol. 2004; 287:G1227–37. https://doi.org/10.1152/ajpgi.00253.2004 [PubMed]
• 95. Groner B, von Manstein V. Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition. Mol Cell Endocrinol. 2017; 451:1–14. https://doi.org/10.1016/j.mce.2017.05.033 [PubMed]
• 96. Ying J, Qiu X, Lu Y, Zhang M. SOCS1 and its Potential Clinical Role in Tumor. Pathol Oncol Res. 2019; 25:1295–301. https://doi.org/10.1007/s12253-019-00612-5 [PubMed]
• 97. Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle JN, Yoshimura A. The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J. 1999; 18:1309–20. https://doi.org/10.1093/emboj/18.5.1309 [PubMed]
• 98. Sugase T, Takahashi T, Serada S, Nakatsuka R, Fujimoto M, Ohkawara T, Hara H, Nishigaki T, Tanaka K, Miyazaki Y, Makino T, Kurokawa Y, Yamasaki M, et al. Suppressor of cytokine signaling-1 gene therapy induces potent antitumor effect in patient-derived esophageal squamous cell carcinoma xenograft mice. Int J Cancer. 2017; 140:2608–21. https://doi.org/10.1002/ijc.30666 [PubMed]
• 99. Yang Y, Jin G, Liu H, Liu K, Zhao J, Chen X, Wang D, Bai R, Li X, Jang Y, Lu J, Xing Y, Dong Z. Metformin inhibits esophageal squamous cell carcinoma-induced angiogenesis by suppressing JAK/STAT3 signaling pathway. Oncotarget. 2017; 8:74673–87. https://doi.org/10.18632/oncotarget.20341 [PubMed]
• 100. Tian F, Yang X, Liu Y, Yuan X, Fan T, Zhang F, Zhao J, Lu J, Jiang Y, Dong Z, Yang Y. Constitutive activated STAT3 is an essential regulator and therapeutic target in esophageal squamous cell carcinoma. Oncotarget. 2017; 8:88719–29. https://doi.org/10.18632/oncotarget.20838 [PubMed]
• 101. De Luca A, Maiello MR, D’Alessio A, Pergameno M, Normanno N. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets. 2012 (Suppl 2); 16:S17–27. https://doi.org/10.1517/14728222.2011.639361 [PubMed]
• 102. Nan P, Wang T, Li C, Li H, Wang J, Zhang J, Dou N, Zhan Q, Ma F, Wang H, Qian H. MTA1 promotes tumorigenesis and development of esophageal squamous cell carcinoma via activating the MEK/ERK/p90RSK signaling pathway. Carcinogenesis. 2020; 41:1263–72. https://doi.org/10.1093/carcin/bgz200 [PubMed]
• 103. Riquelme E, Behrens C, Lin HY, Simon G, Papadimitrakopoulou V, Izzo J, Moran C, Kalhor N, Lee JJ, Minna JD, Wistuba II. Modulation of EZH2 Expression by MEK-ERK or PI3K-AKT Signaling in Lung Cancer Is Dictated by Different KRAS Oncogene Mutations. Cancer Res. 2016; 76:675–85. https://doi.org/10.1158/0008-5472.CAN-15-1141 [PubMed]
• 104. Ebi H, Costa C, Faber AC, Nishtala M, Kotani H, Juric D, Della Pelle P, Song Y, Yano S, Mino-Kenudson M, Benes CH, Engelman JA. PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1. Proc Natl Acad Sci USA. 2013; 110:21124–29. https://doi.org/10.1073/pnas.1314124110 [PubMed]
• 105. Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov. 2014; 13:928–42. https://doi.org/10.1038/nrd4281 [PubMed]
• 106. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007; 26:3291–310. https://doi.org/10.1038/sj.onc.1210422 [PubMed]
• 107. Xie X, Zu X, Liu F, Wang T, Wang X, Chen H, Liu K, Wang P, Liu F, Zheng Y, Bode AM, Dong Z, Kim DJ. Purpurogallin is a novel mitogen-activated protein kinase kinase 1/2 inhibitor that suppresses esophageal squamous cell carcinoma growth in vitro and in vivo. Mol Carcinog. 2019; 58:1248–59. https://doi.org/10.1002/mc.23007 [PubMed]
• 108. Kim WH, Song HO, Choi HJ, Bang HI, Choi DY, Park H. Ethyl gallate induces apoptosis of HL-60 cells by promoting the expression of caspases-8, -9, -3, apoptosis-inducing factor and endonuclease G. Int J Mol Sci. 2012; 13:11912–22. https://doi.org/10.3390/ijms130911912 [PubMed]
• 109. Wang HR, Sui HC, Ding YY, Zhu BT. Stimulation of the Production of Prostaglandin E₂ by Ethyl Gallate, a Natural Phenolic Compound Richly Contained in Longan. Biomolecules. 2018; 8:91. https://doi.org/10.3390/biom8030091 [PubMed]
• 110. Kalaivani T, Rajasekaran C, Mathew L. Free radical scavenging, cytotoxic, and hemolytic activities of an active antioxidant compound ethyl gallate from leaves of Acacia nilotica (L.) Wild. Ex. Delile subsp. indica (Benth.) Brenan. J Food Sci. 2011; 76:T144–49. https://doi.org/10.1111/j.1750-3841.2011.02243.x [PubMed]
• 111. Liu F, Zu X, Xie X, Liu K, Chen H, Wang T, Liu F, Bode AM, Zheng Y, Dong Z, Kim DJ. Ethyl gallate as a novel ERK1/2 inhibitor suppresses patient-derived esophageal tumor growth. Mol Carcinog. 2019; 58:533–43. https://doi.org/10.1002/mc.22948 [PubMed]
• 112. Wiggin GR, Soloaga A, Foster JM, Murray-Tait V, Cohen P, Arthur JS. MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts. Mol Cell Biol. 2002; 22:2871–81. https://doi.org/10.1128/MCB.22.8.2871-2881.2002 [PubMed]
• 113. Soloaga A, Thomson S, Wiggin GR, Rampersaud N, Dyson MH, Hazzalin CA, Mahadevan LC, Arthur JS. MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14. EMBO J. 2003; 22:2788–97. https://doi.org/10.1093/emboj/cdg273 [PubMed]
• 114. Zhang C, Zhang J, Wu Q, Xu B, Jin G, Qiao Y, Zhao S, Yang Y, Shang J, Li X, Liu K. Sulforaphene induces apoptosis and inhibits the invasion of esophageal cancer cells through MSK2/CREB/Bcl-2 and cadherin pathway in vivo and in vitro. Cancer Cell Int. 2019; 19:342. https://doi.org/10.1186/s12935-019-1061-1 [PubMed]
• 115. Xie X, Liu K, Liu F, Chen H, Wang X, Zu X, Ma X, Wang T, Wu Q, Zheng Y, Bode AM, Dong Z, Kim DJ. Gossypetin is a novel MKK3 and MKK6 inhibitor that suppresses esophageal cancer growth in vitro and in vivo. Cancer Lett. 2019; 442:126–36. https://doi.org/10.1016/j.canlet.2018.10.016 [PubMed]
• 116. Lund ME, Campbell DH, Walsh BJ. The Role of Glypican-1 in the Tumour Microenvironment. Adv Exp Med Biol. 2020; 1245:163–76. https://doi.org/10.1007/978-3-030-40146-7_8 [PubMed]
• 117. Hara H, Takahashi T, Serada S, Fujimoto M, Ohkawara T, Nakatsuka R, Harada E, Nishigaki T, Takahashi Y, Nojima S, Miyazaki Y, Makino T, Kurokawa Y, et al. Overexpression of glypican-1 implicates poor prognosis and their chemoresistance in oesophageal squamous cell carcinoma. Br J Cancer. 2016; 115:66–75. https://doi.org/10.1038/bjc.2016.183 [PubMed]
• 118. Li J, Chen Y, Zhan C, Zhu J, Weng S, Dong L, Liu T, Shen X. Glypican-1 Promotes Tumorigenesis by Regulating the PTEN/Akt/β-Catenin Signaling Pathway in Esophageal Squamous Cell Carcinoma. Dig Dis Sci. 2019; 64:1493–502. https://doi.org/10.1007/s10620-019-5461-9 [PubMed]
• 119. Harada E, Serada S, Fujimoto M, Takahashi Y, Takahashi T, Hara H, Nakatsuka R, Sugase T, Nishigaki T, Saito Y, Hiramatsu K, Nojima S, Mitsuo R, et al. Glypican-1 targeted antibody-based therapy induces preclinical antitumor activity against esophageal squamous cell carcinoma. Oncotarget. 2017; 8:24741–52. https://doi.org/10.18632/oncotarget.15799 [PubMed]
• 120. De Luca A, Cerrato V, Fucà E, Parmigiani E, Buffo A, Leto K. Sonic hedgehog patterning during cerebellar development. Cell Mol Life Sci. 2016; 73:291–303. https://doi.org/10.1007/s00018-015-2065-1 [PubMed]
• 121. Cortes JE, Gutzmer R, Kieran MW, Solomon JA. Hedgehog signaling inhibitors in solid and hematological cancers. Cancer Treat Rev. 2019; 76:41–50. https://doi.org/10.1016/j.ctrv.2019.04.005 [PubMed]
• 122. van den Brink GR. Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol Rev. 2007; 87:1343–75. https://doi.org/10.1152/physrev.00054.2006 [PubMed]
• 123. Alvarez-Trotta A, Wang Z, Shersher E, Li B, Long J, Lohse I, Wahlestedt C, El-Rifai W, Robbins DJ, Capobianco AJ. The bromodomain inhibitor IBET-151 attenuates vismodegib-resistant esophageal adenocarcinoma growth through reduction of GLI signaling. Oncotarget. 2020; 11:3174–87. https://doi.org/10.18632/oncotarget.27699 [PubMed]
• 124. Teichman J, Dodbiba L, Thai H, Fleet A, Morey T, Liu L, McGregor M, Cheng D, Chen Z, Darling G, Brhane Y, Song Y, Espin-Garcia O, et al. Hedgehog inhibition mediates radiation sensitivity in mouse xenograft models of human esophageal adenocarcinoma. PLoS One. 2018; 13:e0194809. https://doi.org/10.1371/journal.pone.0194809 [PubMed]
• 125. Yang L, Wang LS, Chen XL, Gatalica Z, Qiu S, Liu Z, Stoner G, Zhang H, Weiss H, Xie J. Hedgehog signaling activation in the development of squamous cell carcinoma and adenocarcinoma of esophagus. Int J Biochem Mol Biol. 2012; 3:46–57. [PubMed]
• 126. Kelly RJ, Ansari AM, Miyashita T, Zahurak M, Lay F, Ahmed AK, Born LJ, Pezhouh MK, Salimian KJ, Ng C, Matsangos AE, Stricker-Krongrad AH, Mukaisho KI, et al. Targeting the Hedgehog Pathway Using Itraconazole to Prevent Progression of Barrett’s Esophagus to Invasive Esophageal Adenocarcinoma. Ann Surg. 2019. [Epub ahead of print]. https://doi.org/10.1097/SLA.0000000000003455 [PubMed]
• 127. Wang L, Jin JQ, Zhou Y, Tian Z, Jablons DM, He B. Gli is activated and promotes epithelial-mesenchymal transition in human esophageal adenocarcinoma. Oncotarget. 2017; 9:853–65. https://doi.org/10.18632/oncotarget.22856 [PubMed]
• 128. Sims-Mourtada J, Izzo JG, Apisarnthanarax S, Wu TT, Malhotra U, Luthra R, Liao Z, Komaki R, van der Kogel A, Ajani J, Chao KS. Hedgehog: an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response. Clin Cancer Res. 2006; 12:6565–72. https://doi.org/10.1158/1078-0432.CCR-06-0176 [PubMed]
• 129. Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets. 2008; 8:187–98. https://doi.org/10.2174/156800908784293659 [PubMed]
• 130. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004; 30:193–204. https://doi.org/10.1016/j.ctrv.2003.07.007 [PubMed]
• 131. Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin Cancer Biol. 2019; 59:125–32. https://doi.org/10.1016/j.semcancer.2019.07.009 [PubMed]
• 132. Shi JJ, Xing H, Wang YX, Zhang X, Zhan QM, Geng MY, Ding J, Meng LH. PI3Kα inhibitors sensitize esophageal squamous cell carcinoma to radiation by abrogating survival signals in tumor cells and tumor microenvironment. Cancer Lett. 2019; 459:145–55. https://doi.org/10.1016/j.canlet.2019.05.040 [PubMed]
• 133. Song M, Liu X, Liu K, Zhao R, Huang H, Shi Y, Zhang M, Zhou S, Xie H, Chen H, Li Y, Zheng Y, Wu Q, et al. Targeting AKT with Oridonin Inhibits Growth of Esophageal Squamous Cell Carcinoma In Vitro and Patient-Derived Xenografts In Vivo. Mol Cancer Ther. 2018; 17:1540–53. https://doi.org/10.1158/1535-7163.MCT-17-0823 [PubMed]
• 134. Liu X, Song M, Wang P, Zhao R, Chen H, Zhang M, Shi Y, Liu K, Liu F, Yang R, Li E, Bode AM, Dong Z, Lee MH. Targeted therapy of the AKT kinase inhibits esophageal squamous cell carcinoma growth in vitro and in vivo. Int J Cancer. 2019; 145:1007–19. https://doi.org/10.1002/ijc.32285 [PubMed]
• 135. Liu F, Zu X, Xie X, Zhang Y, Liu K, Chen H, Wang T, Bode AM, Dong Z, Kim DJ. Scutellarin Suppresses Patient-Derived Xenograft Tumor Growth by Directly Targeting AKT in Esophageal Squamous Cell Carcinoma. Cancer Prev Res (Phila). 2019; 12:849–60. https://doi.org/10.1158/1940-6207.CAPR-19-0244 [PubMed]
• 136. Prager GW, Poettler M, Unseld M, Zielinski CC. Angiogenesis in cancer: Anti-VEGF escape mechanisms. Transl Lung Cancer Res. 2012; 1:14–25. https://doi.org/10.3978/j.issn.2218-6751.2011.11.02 [PubMed]
• 137. Itatani Y, Kawada K, Yamamoto T, Sakai Y. Resistance to Anti-Angiogenic Therapy in Cancer-Alterations to Anti-VEGF Pathway. Int J Mol Sci. 2018; 19:1232. https://doi.org/10.3390/ijms19041232 [PubMed]
• 138. Khan U, Shah MA. Ramucirumab for the treatment of gastric or gastro-esophageal junction cancer. Expert Opin Biol Ther. 2019; 19:1135–41. https://doi.org/10.1080/14712598.2019.1656715 [PubMed]
• 139. Wei B, Wang Y, Wang J, Cai X, Xu L, Wu J, Wang Y, Liu W, Gu Y, Guo W, Xu Q. Apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer via the Akt/β-catenin pathway. Cancer Cell Int. 2020; 20:198. https://doi.org/10.1186/s12935-020-01290-z [PubMed]
• 140. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, et al, and REGARD Trial Investigators. 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. https://doi.org/10.1016/S0140-6736(13)61719-5 [PubMed]
• 141. Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, et al, and RAINBOW Study Group. 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; 15:1224–35. https://doi.org/10.1016/S1470-2045(14)70420-6 [PubMed]
• 142. Yanwei L, Feng H, Ren P, Yue J, Zhang W, Tang P, Shang X, Pang Q, Liu D, Chen C, Pan Z, Tao YZ. Safety and Efficacy of Apatinib Monotherapy for Unresectable, Metastatic Esophageal Cancer: A Single-Arm, Open-Label, Phase II Study. Oncologist. 2020; 25:e1464–72. https://doi.org/10.1634/theoncologist.2020-0310 [PubMed]
• 143. Liang LJ, Wen YX, Xia YY, Wang L, Fei JY, Jiang XD. Apatinib combined with docetaxel as a salvage treatment for metastatic esophageal squamous cancer: a case report. Onco Targets Ther. 2018; 11:5821–26. https://doi.org/10.2147/OTT.S174429 [PubMed]
• 144. Steins A, Ebbing EA, Pistorius MC, Waasdorp C, Krishnadath KK, Medema JP, Wilmink JW, Mathôt RA, Bijlsma MF, van Laarhoven HW. Systemic effects of angiogenesis inhibition alter pharmacokinetics and intratumoral delivery of nab-paclitaxel. Drug Deliv. 2017; 24:1801–10. https://doi.org/10.1080/10717544.2017.1406559 [PubMed]
• 145. Slotta-Huspenina J, Becker KF, Feith M, Walch A, Langer R. Heat Shock Protein 90 (HSP90) and Her2 in Adenocarcinomas of the Esophagus. Cancers (Basel). 2014; 6:1382–93. https://doi.org/10.3390/cancers6031382 [PubMed]
• 146. Yan H, Li B, Fan T, Jiang S, Wang R, Sun M. Clinical significance of serum dynamics of HSP90a level in esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy. Cancer Biomark. 2017; 19:185–92. https://doi.org/10.3233/CBM-160502 [PubMed]
• 147. Ekman S, Bergqvist M, Tell R, Bergström S, Lennartsson J. Hsp90 as a therapeutic target in patients with oesophageal carcinoma. Expert Opin Ther Targets. 2010; 14:317–28. https://doi.org/10.1517/14728221003621278 [PubMed]
• 148. Guan L, Zou Q, Liu Q, Lin Y, Chen S. HSP90 Inhibitor Ganetespib (STA-9090) Inhibits Tumor Growth in c-Myc-Dependent Esophageal Squamous Cell Carcinoma. Onco Targets Ther. 2020; 13:2997–3011. https://doi.org/10.2147/OTT.S245813 [PubMed]
• 149. Gao YB, Chen ZL, Li JG, Hu XD, Shi XJ, Sun ZM, Zhang F, Zhao ZR, Li ZT, Liu ZY, Zhao YD, Sun J, Zhou CC, et al. Genetic landscape of esophageal squamous cell carcinoma. Nat Genet. 2014; 46:1097–102. https://doi.org/10.1038/ng.3076 [PubMed]
• 150. Sawada G, Niida A, Uchi R, Hirata H, Shimamura T, Suzuki Y, Shiraishi Y, Chiba K, Imoto S, Takahashi Y, Iwaya T, Sudo T, Hayashi T, et al. Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population. Gastroenterology. 2016; 150:1171–82. https://doi.org/10.1053/j.gastro.2016.01.035 [PubMed]
• 151. Lubin DJ, Mick R, Shroff SG, Stashek K, Furth EE. The notch pathway is activated in neoplastic progression in esophageal squamous cell carcinoma. Hum Pathol. 2018; 72:66–70. https://doi.org/10.1016/j.humpath.2017.11.004 [PubMed]
• 152. Wang Z, Da Silva TG, Jin K, Han X, Ranganathan P, Zhu X, Sanchez-Mejias A, Bai F, Li B, Fei DL, Weaver K, Carpio RV, Moscowitz AE, et al. Notch signaling drives stemness and tumorigenicity of esophageal adenocarcinoma. Cancer Res. 2014; 74:6364–74. https://doi.org/10.1158/0008-5472.CAN-14-2051 [PubMed]
• 153. Wang Z, Chen J, Capobianco AJ. The Notch signaling pathway in esophageal adenocarcinoma. Cell Mol Biol (Noisy-le-grand). 2015; 61:24–32. [PubMed]
• 154. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004; 4:253–65. https://doi.org/10.1038/nrc1317 [PubMed]
• 155. Stanton RA, Gernert KM, Nettles JH, Aneja R. Drugs that target dynamic microtubules: a new molecular perspective. Med Res Rev. 2011; 31:443–81. https://doi.org/10.1002/med.20242 [PubMed]
• 156. Sheng Y, Liu K, Wu Q, Oi N, Chen H, Reddy K, Jiang Y, Yao K, Li H, Li W, Zhang Y, Saleem M, Ma WY, et al. PPMP, a novel tubulin-depolymerizing agent against esophageal cancer in patient-derived tumor xenografts. Oncotarget. 2016; 7:30977–89. https://doi.org/10.18632/oncotarget.9050 [PubMed]
• 157. Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015; 21:1253–61. https://doi.org/10.1038/nm.3981 [PubMed]
• 158. Renganathan A, Felley-Bosco E. Long Noncoding RNAs in Cancer and Therapeutic Potential. Adv Exp Med Biol. 2017; 1008:199–222. https://doi.org/10.1007/978-981-10-5203-3_7 [PubMed]
• 159. Liu J, Liu ZX, Wu QN, Lu YX, Wong CW, Miao L, Wang Y, Wang Z, Jin Y, He MM, Ren C, Wang DS, Chen DL, et al. Long noncoding RNA AGPG regulates PFKFB3-mediated tumor glycolytic reprogramming. Nat Commun. 2020; 11:1507. https://doi.org/10.1038/s41467-020-15112-3 [PubMed]
• 160. Ebbing EA, Steins A, Fessler E, Stathi P, Lesterhuis WJ, Krishnadath KK, Vermeulen L, Medema JP, Bijlsma MF, van Laarhoven HW. Esophageal Adenocarcinoma Cells and Xenograft Tumors Exposed to Erb-b2 Receptor Tyrosine Kinase 2 and 3 Inhibitors Activate Transforming Growth Factor Beta Signaling, Which Induces Epithelial to Mesenchymal Transition. Gastroenterology. 2017; 153:63–76.e14. https://doi.org/10.1053/j.gastro.2017.03.004 [PubMed]
• 161. Mashimo T, Takizawa A, Kobayashi J, Kunihiro Y, Yoshimi K, Ishida S, Tanabe K, Yanagi A, Tachibana A, Hirose J, Yomoda J, Morimoto S, Kuramoto T, et al. Generation and characterization of severe combined immunodeficiency rats. Cell Rep. 2012; 2:685–94. https://doi.org/10.1016/j.celrep.2012.08.009 [PubMed]
• 162. Miao J, Ying B, Li R, Tollefson AE, Spencer JF, Wold WS, Song SH, Kong IK, Toth K, Wang Y, Wang Z. Characterization of an N-Terminal Non-Core Domain of RAG1 Gene Disrupted Syrian Hamster Model Generated by CRISPR Cas9. Viruses. 2018; 10:243. https://doi.org/10.3390/v10050243 [PubMed]
• 163. Miao JX, Wang JY, Li HZ, Guo HR, Dunmall LSC, Zhang ZX, Cheng ZG, Gao DL, Dong JZ, Wang ZD, Wang YH. Promising xenograft animal model recapitulating the features of human pancreatic cancer. World J Gastroenterol. 2020; 26:4802–16. https://doi.org/10.3748/wjg.v26.i32.4802 [PubMed]
• 164. Lee NP, Chan CM, Tung LN, Wang HK, Law S. Tumor xenograft animal models for esophageal squamous cell carcinoma. J Biomed Sci. 2018; 25:66. https://doi.org/10.1186/s12929-018-0468-7 [PubMed]