p53 molecular approach to diagnosis and treatment of esophageal squamous cell carcinoma

Abstract

We reviewed our research concerning p53 molecules in esophageal squamous cell carcinoma by focusing on the p53 molecular diagnosis and treatment of esophageal squamous cell carcinoma. First, we developed diagnostic tools to analyze serum p53 autoantibodies to detect esophageal squamous cell carcinoma. Positive rate was around 25% to 30% in all patients and around 20% even in stage I patients. Presence of serum p53 antibodies was significantly associated with overexpression of p53 protein in tumor cells. Seropositive patients were more likely than seronegative patients to be resistant to chemotherapy. Monitoring of the titer of serum p53 autoantibodies was useful in predicting patients at high risk of recurrence and/or treatment response. Second, using Ad5CMV-p53 for 10 patients with advanced esophageal squamous cell carcinoma, we carried out a phase I/II study of adenoviral-mediated p53 gene therapy. Although no complete response was observed, local tumor was stabilized in nine patients. No serious adverse events related to Ad5CMV-p53 were observed in these patients. One patient survived for over 5 years after the start of p53 gene therapy. Intratumoral injection of Ad5CMV-p53 is therefore safe, feasible, and biologically active when given in multiple doses to patients with esophageal squamous cell carcinoma. Our observations from these clinical studies indicate that p53 is a useful molecular target both in the diagnosis and in the treatment of esophageal squamous cell carcinoma.

Keywords: autoantibody; esophageal cancer; gene therapy; p53; squamous cell carcinoma.

Figure 1

Comparison of positive rate of serum tumor markers in patients with esophageal squamous cell carcinoma. Positive rates of all patients and that of stage I patients were compared between s‐p53 Abs, carcinoembryonic antigen (CEA), squamous cell carcinoma (SCC)‐Ag and cytokeratin 19 fragment (CYFRA21‐1)

Figure 2

Detection of the early phase of esophageal cancer progression into lamina propria mucosae by serum p53 antibody.17 A, Changes in serum p53 antibody levels before and after endoscopic submucosal dissection (ESD) of esophageal squamous cell carcinoma. Carcinoembryonic antigen (CEA) level was continuously negative. B, Resection specimen after ESD of esophageal squamous cell carcinoma. H&E staining in the ESD specimen. C, p53 immunoreactivity in the ESD specimen

Figure 3

Overall survival curves according to status of serum p53 antibody.21 A, Survival according to postoperative status of serum p53 antibodies. B, Survival of patients positive for serum p53 antibody before surgery. P‐values were calculated by log‐rank test

Figure 4

Overall survival curves according to changes in serum p53 antibody titer in 40 seropositive patients.21 A total of 23 patients showed reduction of serum titer and a total of 17 patients showed no reduction. P‐values were calculated by log‐rank test

Figure 5

Comparisons of positive rates of s‐p53 Abs and carcinoembryonic antigen (CEA) in various cancers13

Figure 6

Survival curves of stage II and stage III patients with colorectal cancer according to various ranges of s‐p53 Abs titers27

Figure 7

Effect of Ad5CMV‐p53 infection on in vivo tumor growth of human esophageal squamous cell carcinoma cell line (T.Tn).29 Established tumors were treated after reaching a size of 200 mm³ with 2 injections delivered on days 14 and 16 of DMEM/F‐12 medium or the virus (total dose 2× 10¹⁰ pfu). Mean tumor volumes per 5 mice following injection are plotted against the number of days since s.c. transplantation. Bars, SD; ●, Ad1.0CMV‐β‐gal; ■, Ad5CMV‐p53; ♦, no treatment;▲, DMEM

Figure 8

Upper thoracic esophageal cancer inoperable because of tracheal invasion. A and C, Complete obstruction is seen before p53 gene transfer. B and D, Esophageal obstruction was reduced after treatment30

Figure 9

A, Overall survival; B, time to local progression; and C, time to metastatic progression of all patients30

Figure 10

Summary of Ad‐CMV vector biodistribution in three patients with esophageal cancer after Ad5CMV‐p53 tumoral injection.31 Black box, Ad5CMV‐p53 positive; crossed box, samples not available; white box, Ad5CMV‐p53 negative. Pt, patient