Table 1.
Association of heparanase, Sulf1, and Sulf2 in solid tumors and hematologic malignancies.
| Enzyme | Cancer | Key scientific finding | Key clinical finding | Reference |
|---|---|---|---|---|
| Heparanase | PNET | HPSE mRNA ↑ by 40-fold in primary tumors and metastatic tumors compared to normal islets | HPSE mRNA was significantly upregulated in PNET patients with primary tumors (*P = 0.046, n = 25) and liver metastases (*P = 0.026, n = 15) compared to normal islet samples from normal islets (n = 4) | (78) |
| Heparanase | OMM | HPSE staining was positive in 81% of tumors (66 of 81 patients) | Median survival time and 5-year survival rate were 12 months and 7.0% in the high-HPSE group, 35 months and 36.4% in the low-HPSE group, 62 months and 53.3% in the no-HPSE group (P = 0.001) | (79) |
| Heparanase | Cervical | HPSE ↑ by 63% (38/60) patients by IHC | Significant correlation with tumor size and clinical stage | (80) |
| Heparanase | Ovarian | Median HPSE serum levels 2.77, 4.86 and 7.68 ng/mL in control, benign and malignant samples respectively | Increased serum HPSE in ovarian cancer patients with distant metastasis (P < 0.05) HPSE (in conjunction with Cathepsin L and MMP-9) elevation possibly useful in determining extent of metastasis before surgery | (81) |
| Heparanase | Oral SCC | HPSE ↑ in 41% (19/46) | Rate of HPSE expression closely related to tumor size, tumor stage, lymphatic metastasis, distant metastasis, pathological and histological stage | (82) |
| Heparanase | Lung* | Adenocarcinomas exhibited strong HPSE expression by IHC | Heparanase expression tended to correlate with tumor node metastasis (TNM) staging in non-small cell lung carcinoma | (83) |
| Heparanase | CCC | HPSE expression from 47 patient samples was significantly associated with PDGFRα expression but not its ligand PDGF | HPSE expression (mRNA) <35th percentile led to median OS 10.2 months versus HPSE >35th percentile lead to median OS 20.1 months | (84) |
| Heparanase | HNSCC | Strong HPSE expression was localized at the invasion front of the tumor and in disseminated tumor cells | Patients lacking HPSE-expressing cells (<5%) in their tumors had a prolonged DFS of 25.8 compared with patients with HPSE-positive tumors (>5%) with mean DFS of 8.2 months. HPSE also higher in lymph nodes | (85) |
| Cellular HPSE expression was detected in 41 of 71 (58%) cases; in particular, UICC IV-stage tumors | Patients with high-level HPSE expression had prolonged overall survival (P = 0.029) and this was associated with low tumor cell proliferation which might outweigh HPSE-induced invasion and migration in late-stage tumors | (86) | ||
| Heparanase | Ewing’s sarcoma | 49% (34/69) Of the cases were scored as low (+1) intensity while 51% (35/69) exhibited a strong (+2) staining intensity | HPSE staining was evident in all biopsies examined, exhibiting a high (+2) staining extent (i.e., >50% of the cells) in the majority (91%) of cases. Possible association to tumor size (P = 0.07), strong staining in 75% of those with large tumors (>10 cm) | (77) |
| STS | High-HPSE expression in 29 (52.7%) primary tumors and 22 specimens (47.8%) in metastatic sites | HPSE expression not correlative with tumor aggressiveness, tumor recurrence or survival | (87) | |
| Heparanase | AML | mRNA and/or protein expression of HPSE revealed low HPSE in ALL (and CLL, NHL) patients and a high expression level in MM and AML patients, versus healthy controls | HPSE mRNA expression was significantly increased in 14/15 patient samples and genotype frequency comparisons revealed a significant association with rs4364254 [chi2 (2d.f.) = 6.226, P = 0.044] in AML patients. HPSE gene mRNA expression was high in AML patients | (88, 89) |
| Sulf1 | Gastric | Sulf1 expression ↑in tumor tissues (P = 0.0002) compared to normal mucosa | Multivariate analysis found Sulf1 is an independent prognostic (P = 0.01) and lymph node metastasis predictive factor (P = 0.0003) in large cohort of patients (450) | (90) |
| Sulf1 | Gastric | Sulf1 protein expression ↓which is discordant with mRNA findings | Despite mRNA expression being ↑in 30% of samples, protein expression ↓in 70% (14/20) of tumor samples | (91) |
| Sulf2 | GBM | Sulf2 may alter PDGFRα signaling/activation to promote tumorigenesis | Sulf2 expression ↑in proneural subtype of GBM (n = 173, P < 0.005) and ↑using IHC in 28 subtyped GBMs demonstrated that proneural and mesenchymal subtypes | (92) |
| Sulf2 | MM | Sulf2 ↑in hyperdiploid group but ↓in groups of patients with Cyclin D1 or MAF translocations | Sulf2 expression in primary MM cells linked to poor prognosis in two independent large cohorts. Sulf2 was independently predictive for OS (P = 0.02) | (93) |
| Sulf2 | OAC/OSCC | Sulf2 detected using IHC on 75 OAC patients and 25 OSCC patients | Majority of OAC and OSCC had Sulf2 staining. For every 10%, ↑in % tumor cells staining for Sulf2, the HR for death ↑by 13% (P = 0.03) | (94) |
| Sulf2 | Various | Sulf2 increased (P = 0.001) compared to normal mucosa | Significant overexpression in uveal melanoma (=0.03), lung adenocarcinoma (P = 0.04) and colorectal carcinoma (P = 0.001) compared to low grade, low expressed and colon adenomas respectively | (93) |
AML, acute myeloid leukemia; CCC, cholangiocarcinoma; CLL, chronic lymphoblastic leukemia; DFS, disease-free survival; GBM, glioblastoma multiforme; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; MM, multiple myeloma; NHL, non-Hodgkin’s lymphoma; OAC, esophageal adenocarcinoma; OMM, oral mucosal melanoma; OSCC, esophageal squamous cell carcinoma; PNET, pancreatic neuroendocrine tumors; SCC, squamous cell carcinoma; STS, soft tissue sarcoma.
*37 Patients, there were 14 adenocarcinomas, 13 squamous cell carcinomas, 5 large cell carcinomas, and 5 small cell carcinomas.