Circulating syndecan-1 and glypican-4 predict 12-month survival in metastatic colorectal cancer patients

Abstract

Cell surface syndecans and glypicans play important roles in the development and prognosis of colorectal cancer (CRC). Their soluble forms from proteoglycan shedding can be detected in blood and have been proposed as new prognostic biomarkers in several cancer entities. However, studies on circulating syndecan-1 (SDC1) and glypican-4 (GPC4) in CRC are limited. We, therefore, evaluated the impact of plasma SDC1 and GPC4 on the prognosis of metastatic (m)CRC patients. The present study included 93 patients with mCRC. The endpoints were progression-free survival (PFS) and overall survival (OS) at 12 months. SDC1 and GPC4 levels were measured in plasma using enzyme-linked immunosorbent assays. Plasma levels of SDC1 and GPC4 were significantly correlated. Significant correlations of these two markers were also found with carcinoembryonic antigen (CEA). Kaplan-Meier curve analyses indicated that PFS and OS probabilities significantly decreased with increasing levels of SDC1 and GPC4, respectively. Multivariable Cox regression analyses showed that both markers were significantly associated with PFS and OS independently from clinicopathological characteristics including CEA. Respective adjusted hazard ratios (HR) together with corresponding 95% confidence intervals for one standard deviation change of SDC1 were 1.32 [1.02-1.84] for PFS and 1.48 [1.01-2.15] for OS. Adjusted HRs [95% confidence intervals] of GPC4 were 1.42 [1.07-1.89] for PFS and 2.40 [1.51-3.81] for OS. Results from area under the receiver operating characteristic curve analyses suggest that GPC4 and SDC1 add additional prognostic values to CEA for OS. In conclusion, we showed significant associations of circulating SDC1 and GPC4 with poor survival of mCRC patients.

Circulating Glypican-4 Is a Predictor of 24-Month Overall Survival in Metastatic Breast Cancer

“…We identified circulating GPC4 as a significant predictor of OS in patients with ER+/HER2− MBC treat-ed with endocrine therapy in combination with CDK4/6 inhibitors. The reported results are in line with a previous study from our research group including patients with metastatic colorectal cancer [14] and demonstrating that shed GPC4 is significantly linked to the prognosis of those patients.…”

“…Consequently, circulating proteoglycans have been proposed as valuable diagnostic and prognostic biomarkers in many diseases, including cancer [12]. Recently, we have identified circulating GPC4 as a biomarker of poor survival in patients with metastatic colorectal cancer [14]. In addition, we showed significant associations between shed GPC4 levels and reduced mortality in coronary angiography patients [15] as well as patients with peripheral artery disease [16].…”

Dichotomous Effects of Glypican-4 on Cancer Progression and Its Crosstalk with Oncogenes

“…Although our understanding of the involvement of GPC4 in cancer is limited, an increasing body of evidence illustrates its essential role in cancer progression. Recent preclinical and clinical reports demonstrate the implications of GPC4 in several cancers, including pancreatic [22], breast [23,24], and colorectal cancer [25]. Further, comprehensive bioinformatic analyses and functional in vitro experiments display a connection between downregulation of GPC4 and the sensitization of pancreatic cancer cells to chemotherapy [22].…”

“…A grand investigation including clinical breast cancer patients, in vivo, ex vivo, and in vitro studies reveals that GPC4 undergoes downregulation in metastatic tumors and that overexpression of GPC4 induces decreased tumorigenicity, i.e., migration and proliferation, in vitro in metastatic cells as well as in vivo in nude mice [23]. Also, two comprehensive clinical investigations demonstrate increased levels of plasma GPC4 in colorectal and metastatic breast cancer patients [24,25]. The increased plasma level of GPC4 in these cancers was found to be associated with poor patient survival [24,25].…”

Attenuation of cancer proliferation by suppression of glypican-1 and its pleiotropic effects in neoplastic behavior

“…Intense research on the role of individual GPC in specific cancers has revealed new insights in the mechanisms of action and roles in neoplastic behavior [ 1 – 3 ]. Recent data from retrospective and prospective clinical studies point out the therapeutic value of GPCs, as well as their potential as putative biomarkers and prognostic factors in several cancer types [ 4 – 6 ]. An organized evaluation of the impact of each individual GPC in cancer has only been performed for glypican 2 (GPC2) [ 7 ].…”