its convenience and low cost. However, the limited specificity of such markers has been widely recognized. When a tumor marker is detected but the organ specificity of that marker is poor, it is not possible to determine which organ has cancer. For example, CEA is a tumor marker for breast cancer, but it is also expressed at high levels in colorectal cancer, stomach cancer, and pancreatic cancer (Vaidyanathan and Vasudevan 2012). Therefore further tests are required, which results in an increased burden on the patient. Because of these problems, screening for new molecular biomarkers to be used in liquid biopsy is underway: the aim is to develop more accurate methods for early cancer diagnosis.
The discovery of new molecular biomarkers overcomes the drawbacks, thanks to the intimate association of these se biomarkers with cancer-related genetic alterations. The proteins on the surfaces of exosomes are potential cancer biomarkers that can allow early tumor diagnosis (Table 3.2). Glypican-1 (GPC1) (+) exosomes could distinguish healthy subjects from patients with pancreatic cancer (Melo et al. 2015). The percentage of GPC1 (+) exosomes was markedly increased in plasma from patients with pancreatic cancer; however, they were decreased to normal levels after surgery. It was also reported that the exosome protein survivin-2B was a good biomarker for breast cancer diagnosis, and the level of TRIM3 protein in serum exosomes was decreased in gastric cancer patients (Khan et al. 2012; Fu et al. 2018).
Since exosomes are surrounded by a lipid bilayer membrane, they are not easily degraded even in those body fluids that contain many digestive enzymes. Therefore an EV-associated RNA is highly stable and makes an ideal noninvasive biomarker for cancer diagnosis. The most abundant type of RNA in exosomes is miRNA; consequently liquid biopsies using miRNAs in exosomes as cancer biomarkers have been developed in various cancer types (Table 3.3).
Increasing evidence has accumulated that EV-associated miRNAs may also prove clinically useful other than as cancer biomarkers—namely as biomarkers for non-cancer diseases. These diseases include pathogenic inflammation, infection, and chronic diseases. However, the disease-specific exosome cargo remains to be fully elucidated and validated.
Recently EV-associated miRNAs were identified as biomarkers for Alzheimer’s disease and Parkinson’s disease.
Table 3.3 Summary of exosomal proteins for early tumor diagnosis.
| Type of cancer | Protein | Reference |
|---|---|---|
| Colorectal cancer | Copine III (CPNE3) | (Sun et al. 2019) |
| CD147 | (Tian et al. 2018) | |
| CD147 | (Yoshioka et al. 2014) | |
| Gastric cancer | HER-2/neu, EMMPRIN, MAGE-1, C-MET | (Baran et al. 2010) |
| TRIM3 | (Fu et al. 2018) | |
| Lung adenocarcinoma | CD91, CD317, ITA2B | (Ueda et al. 2014) |
| EGFR, KRAS, claudins and RAB-family proteins | (Clark et al. 2016) | |
| CD151, CD171 and tetraspanin 8 | (Sandfeld-paulsen et al. 2016) | |
| Melanoma | Caveolin | (Logozzi et al. 2009) |
| Met | (Peinado et al. 2012) | |
| Pancreatic ductal adenocarcinoma | GPC-1 | (Melo et al. 2015) |
| Prostate cancer | PSA | (Mizutani et al. 2014) |
| ephrinA2 | (Li et al. 2018) | |
| Survivin | (Khan et al. 2012) | |
| Renal cell carcinoma | MMP-9, DKP4, EMMPRIN, PODXL | (Raimondo et al. 2013) |
Table 3.3 Summary of exosomal miRNAs for early tumor diagnosis.
| Type of cancer | Protein | Reference |
|---|---|---|
| Breast cancer | miR-101, miR-372, miR-373 | (Eichelser et al. 2014) |
| Cervical squamous cell carcinoma | miR-221-3p | (Zhou et al. 2019) |
| Colorectal carcinoma | miR-6803-5p | (Yan et al. 2018) |
| Endometrial cancer | miR-200c-3p | (Srivastava et al. 2018) |
| Glioblastoma multiforme | miR-320 and miR-574-3p | (Manterola et al. 2014) |
| Hepatocellular carcinoma | miR-21 and miR-144 | (Pu et al. 2018) |
| Lung cancer | miR139-5p, miR-200b-5p, miR-378a, and miR-379 | (Cazzoli et al. 2013) |
| let-7g-5p, miR-24-3p, and miR-233-3p | (Rodriguez et al. 2014) | |
| Ovarian cancer | miR-21, miR-141, miR-200a, miR-200c, miR203, miR-205, miR-214 | (Taylor and Gercel-taylor 2008) |
| Pancreatic cancer | miR-1246, miR-3976, miR-4306, and miR-4644 | (Madhavan et al. 2015) |
| miR-17-5p and miR21 | (Que et al. 2013) | |
| Prostate cancer | miR-141 | (Li et al. 2016) |
Toxicology Biomarkers
Various chemical substances and drugs that are indispensable
