Highly Sensitive Detection of Melanoma at an Early Stage Based on the Increased Serum Secreted Protein Acidic and Rich in Cysteine and Glypican-3 Levels

Abstract

Purpose: There are no available tumor markers detecting primary melanoma at an early stage.The identification of such serum markers would be of significant benefit for an early diagnosis of melanoma.We recently identified glypican-3 (GPC3) as a novel tumor marker but could diagnose only 40% of melanomas. Thereby, we focused out attention on secreted protein acidic and rich in cysteine (SPARC) overexpressed in melanoma as another candidate for tumor marker. Experimental Design: Secreted SPARC protein was quantified using ELISA in the sera from109 melanoma patients, five patients with large congenital melanocytic nevus, 61 age-matched healthy donors, and 13 disease-free patients after undergoing a surgical removal.We also quantified GPC3 and 5-S-cysteinyldopa in the same serum samples and compared these markers for their diagnostic value. Results: The serum SPARC concentrations in melanoma patients were greater than those in healthy donors (P = 0.001). When we fixed a cutoff value at the mean concentration plus 2 SD of the healthy donors, the serum SPARC was found to have increased in the sera of 36 of the 109 (33%) melanoma patients, whereas there were three (4.9%) false-positive cases of 61 healthy donors. Surprisingly, 19 of 36 patients showing increased SPARC levels were in stages 0 to II. The serum SPARC level decreased under the cutoff level in 10 of 13 patients after surgical removal. Using SPARC and GPC3 in combination thus enabled us to diagnose 47 of 75 (66.2%) melanoma patients at an early stage (0-II). Conclusions: SPARC or its combination with GPC3 is thus considered a potentially useful tumor marker, especially for melanoma at an early stage.

Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis

“…Paracrine functions attributed so far to SPARC in melanoma were related to inhibition of polymorphonuclear leukocyte recruitment 43 , and inhibition of proliferation and migration capacities of endothelial cells in vitro 45 . Supported by previous evidence that elevated SPARC is associated with the occurrence of distant metastases and poor survival in melanoma patients 30,31 , our findings functionally demonstrate that SPARC mediates critical tumour cell-endothelium communications through a novel paracrine function on lung capillaries culminating in breaching vascular integrity during metastatic dissemination. Clinically, our findings are underlined by the high expression of SPARC that we observed in pulmonary metastases of melanoma biopsies.…”

“…Despite earlier studies that have correlated levels of SPARC to the early stages of malignant melanomas and found expression of SPARC associated with invasion and poor clinical income [30][31][32] , no evidence has been provided for an association of SPARC with distant melanoma metastases. To determine the clinical relevance of our findings, we investigated SPARC expression in human melanoma lung metastases and amounts of circulating SPARC in blood from patients with stage 4 metastatic disease.…”

Biomarkers for Melanoma Diagnosis and the Technologies Used to Identify Them

“…Glypican-3 (GPC3) is a membrane-bound heparin sulfate proteoglycan which is overexpressed in several tumors. It has been suggested that GPC3 may be a useful early stage biomarker for patients with the early stages of the disease (0 -II) (Nakatsura et al, 2004;Ikuta et al, 2005). Moreover, cyclooxygenase-2 (COX-2) (Chwirot and Kuźbicki, 2007), serum amyloid A (SAA) (Mian et al, 2005;Findeisen et al, 2009) and DNA methylation profiling (Conway et al, 2011) can be used to distinguish between early melanomas and benign nevi.…”

Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer

“…During hepatic carcinogenesis, GPC3 have been reported to reappear in HCC and to be released into serum (12,13,15,26). Its expression is also detected in melanoma (27)(28)(29). The functions of GPC3 in cancer cells are still unclear.…”