Table 2.
Studies that have shown HERV-K expression as a biomarker for cancer screening and as an immunotherapeutic target.
| Cancer | Study (Year) | Approach | Main Findings | Reference |
|---|---|---|---|---|
| Breast cancer | Golan, M. (2008) |
The HERV-K RT expression was examined in 110 paraffin sections from breast carcinoma patients. | HERV-K RT expression correlated with poor prognosis in disease-free patients that go on to develop disease, suggesting HERV-K could be an early prognostic biomarker for breast cancer | [60] |
| Wang-Johanning, F. (2012) |
Human breast tissues and peripheral blood mononuclear cells from breast cancer patients and health women were used to analyze anti-HERV Env antibody and T-cell immune responses. | Breast cancer patients show HERV-specific antibody and T-cell immune responses, as well as proinflammatory cytokine production. The HERV-K-specific CD8 T-cell immune response was able to lyse breast cancer cells expressing HERV-K Env. | [16] | |
| Wang-Johanning, F. (2012) |
The antitumor effect from anti-HERV-K Env monoclonal antibody was analyzed in vitro by quantifying cellular growth and apoptosis in breast cancer cells. In vivo, the tumor growth was analyzed using a mouse xenograft breast cancer model. | Anti HERV-K Env antibody shows antitumor effect. The antibody was able to inhibit cellular growth and induce apoptosis from breast cancer cells in vitro and in vivo. | [105] | |
| Wang-Johanning, F. (2013) |
HERV-K mRNA and anti-HERV-K Env antibody were analyzed in serum samples collected from healthy women and breast cancer women patients. ELISA assay and real-time PCR were used to detect the antibody titer and the levels of HERV-K mRNA, respectively. | Anti-HERV-K Env antibody shows a diagnostic value compared to mammograms. Besides, HERV-K gag mRNA and Gag antibody showed sensitivity and specificity to be used as screening test to early-stage breast cancer diagnosis. | [64] | |
| Zhou, F. (2015) |
The chimeric antigen receptor (CAR) specific for HERV-K Env was generated using anti-HERV-K Env antibody. Its antitumor effect was evaluated in vitro and in vivo, using breast cancer cell lines and xenograft breast cancer models, respectively. |
HERV-K CAR T-cells showed a tumor-specific cytotoxicity in breast cancer cell lines and in a xenograft mouse breast cancer model. HERV-K CAR T-cells were also able to prevent tumor metastasis. | [108] | |
| Johanning, G.L. (2017) |
A total of 512 breast cancer samples (117 basal, 53 Her2-enriched, 212 Luminal A and 130 Luminal B) deposited in the Cancer Genome Atlas were used to analyze four HERV-K loci expressions (HERV-K108 (7p22.1), HERV-K109 (6q14.1), HERV-K113 (19p12b) and HERV-K115 (8p23.1)) in breast cancer patients. | Four HERV loci were upregulated in the basal subtype (poor prognosis breast cancer subtype). HERV-K Env expression was significantly overexpressed in basal tumors in comparison with other upregulated HERV-K genes. | [63] | |
| Melanoma | Schiavetti, F. (2002) |
Peripheral blood mononuclear cells from melanoma patients treated with MAGE peptides and that showed tumor regression were isolated for identification of the antigen recognized by their CD8 T-cells. | Melanoma patients vaccinated with MAGE peptides are able to develop cytotoxic CD8 T-cells against HERV-K and to lyse melanoma cells in vitro. | [112] |
| Büscher, K. (2006) |
Melanoma biopsies and serum samples from melanoma patients were collected to analyze the anti HERV-K antibody and env, rec and np9 HERV-K expression. | Expression of both env and rec were detected in 39% of the melanoma samples and in 40% of the cell lines. The np9 was detected in 29% melanoma samples and in 21% of the cell lines. Anti-HERV-specific Env antibodies were also detected in melanoma patients, however anti HERV-K Np9 and Rec antibodies were not identified. Immunosuppressive Env protein activity and release of virus particles were reported in vitro. |
[113] | |
| Humer, J. (2006) |
Serum samples from healthy and melanoma patients from stage I to stage IV were used to analyze anti HERV-K antibodies in melanoma patients. | Serum samples from melanoma patients show statistically significant differences in seroprevalence of anti-HERV-K Env antibody when compared to healthy subjects. | [114] | |
| Hahn, S. (2008) |
Serum samples from healthy and melanoma patients were used to analyze anti HERV-K Gag and Env antibodies | Melanoma patients showed anti-HERV-K Gag and Env antibodies levels in the sera. Besides, patients with Anti HERV antibody show a significantly decreased disease-specific overall survival (stage I–IV). | [115] | |
| Krishnamurthy, J. (2015) |
Chimeric antigen receptor (CAR) specific to HERV-K Env (K-CAR) were analyzed to kill melanoma cells in vivo using mouse xenograft melanoma model. | HERV-K Env CAR T-cell showed significant antitumor effect in melanoma in vivo, reducing primary tumor and metastatic burden in the mouse xenograft model | [116] | |
| Prostate cancer | Reis, B.S. (2013) |
HERV-K gag expression was analyzed in vitro using tissues (normal and tumor) and cell line. Anti HERV-K Gag antibody was also analyzed using serum samples from prostate cancer patients and healthy subjects. | HERV-K gag expression was upregulated in prostate cancer tissues and its expression was regulated both by demethylation and by androgen stimulation. Anti-HERV-K Gag antibody was also most frequent in serum from patients with advanced prostate cancer (stage III-IV) when compared to early prostate cancer (stages I-II), and it was correlated with worse survival. | [117] |
| Wallace, T. A. (2014) |
A total of 429 blood samples from African–American and European–American healthy men (n = 135) and those with prostate cancer (n = 294) were used to evaluate HERV-K gag mRNA and Env protein expression by quantitative real-time PCR and immunohistochemistry, respectively. | HERV-K Env protein was upregulated in prostate patients; however African–American patients showed higher expression than European–American patients. High HERV-K gag expression showed 12.87 fold increased odds (95% confidence interval 6.3–26.25) of being diagnosed with prostate cancer in comparison to patients that showed lower expression. HERV-K gag expressions were also associated with older age and smoking status, factors associated with risk of more aggressive prostate cancer disease. | [118] | |
| Rastogi, A. (2016) |
Serum samples from 93 prostate cancer patients and 37 healthy subjects were used to analyze the autoantibody detection panel containing ERG, AMACR, C-MYC and HERV-K Gag proteins. | ERG, AMACR, and HERV-K Gag autoantibody detection were able to differentiate prostate cancer patients from healthy subjects. | [119] | |
| Germ cell tumors | Kleiman, A. (2004) |
Serum samples from germ cell tumor patients and control donors were collected. The anti-HERV-K Gag and anti-HERV-K Env were detected and clinical analyses were performed | Anti-HERV-K antibodies were detected in 67% of patients. Serological response was associated with clinical manifestation and cancer therapy success. The antibodies may have an important positive prognostic value to chemotherapy. | [120] |
| Ovarian Cancer | Rycaj, K. (2014) |
HERV-K expression was analyzed in blood, cancer and normal tissue samples from patients with ovarian cancer and benign diseases. The anti-HERV-K antibodies were investigated in blood samples. PBMC was isolated and in vitro HERV-K Env antigen stimulation was performed. | HERV-K expression was higher in ovarian cancer in comparison to normal and adjacent normal tissues. Moreover, RT protein activity and anti-HERV-K antibodies were detected in blood from ovarian cancer patients. The immune HERV-K-specific T-cells, generated through autologous dendritic cell stimulation by HERV-K Env antigens, showed T-cell proliferation and cytotoxic T-lymphocyte activity against ovarian cancer cells. | [107] |
| Pancreatic cancer | Li, M. (2017) |
Pancreatic cancer cell lines, biopsy tissue and patient sera were used for HERV-K expression analyses, virus-like particle detection and knockdown of HERV-K env to analyze the role of HERV-K expression in pancreatic cancer. In addition, an in vivo model was used to analyze the effect of HERV-K knockdown. | HERV-K expression and RT activity were shown in pancreatic cells, cancer tissue and patient sera. Virus-like particles were observed in cell culture supernatants. Moreover, knockdown of HERV-K env expression downregulated the RAS-ERK-RSK signaling pathway, important for cancer progression. The findings suggested that HERV-K proteins can be used as biomarkers and as a target to cancer immunotherapy. | [83] |
| Schmitz-Winnenthal, F.H. (2007) |
A total of 130 pancreatic adenocarcinoma tumors and 23 control tissue samples were collected from patients with chronic pancreatitis and from cadaveric donors. Tumor-associated antigen expression of 10 genes, including HERV-K, was assessed by PCR. | HERV-K expression showed a relatively high prevalence, with positivity in 23% of cases, which may be a tumor-associated antigen candidate for specific cancer immunotherapy. | [121] | |
| Hepatocellular Carcinoma (HCC) | Ma, W. (2016) |
A total of 84 HCC and normal adjacent tissue samples were collected to detect HERV-K expression by quantitative real-time PCR and clinical correlation analysis was performed. | HEVR-K levels were significantly increased in HCC and were associated with cirrhosis, tumor differentiation and TNM staging. Higher HERV-K expression was reported with poorer cancer prognosis. In addition, HERV-K expression demonstrated diagnostic accuracy (74.7% sensitivity and 67.8% specificity), which may be used as a prognostic biomarker for HCC. | [122] |