Desmocollin-3 and Cancer

Desmocollin-3[DSC3] is one of the adhesion molecules of cadher in super family found in desmosome and is a major adhesive force of epithelial cells [1-6]. DSC3 is a transmembrane calcium-dependent glycoprotein produced by the endoplasmic reticulum,encoded by the DSC3 gene. DSC3 is expressed, mainly in basal and immediate suprabasal layers of the stratified squamous epithelia [7] like buccal mucosa, esophagus, cervix, fore skin tongue, trachea etc. [3,8]. As an adhesion molecule, DSC3 provides homophilic adhesion i.e. cells expressing DSC3 will adhere to each other at the site of expression but not with others; it also works as a receptor as well as ligand to participate in cell signaling [9].


Introduction
Desmocollin-3[DSC3] is one of the adhesion molecules of cadher in super family found in desmosome and is a major adhesive force of epithelial cells [1][2][3][4][5][6]. DSC3 is a transmembrane calcium-dependent glycoprotein produced by the endoplasmic reticulum,encoded by the DSC3 gene. DSC3 is expressed, mainly in basal and immediate suprabasal layers of the stratified squamous epithelia [7] like buccal mucosa, esophagus, cervix, fore skin tongue, trachea etc. [3,8]. As an adhesion molecule, DSC3 provides homophilic adhesion i.e. cells expressing DSC3 will adhere to each other at the site of expression but not with others; it also works as a receptor as well as ligand to participate in cell signaling [9].

Desmocollin-3 and Cancer:
Desmosomal abnormalities are seen in cancer, as are alterations in DCS3 expression. In many epithelial cancers, DSC3 expression either over expressed or absent. DSC3 expression is not seen in many cancers e.g. adenocarcinoma of lung, breast, prostate cancer wherein there is mutation of P53 or hyper methylation. DSC3 was first cloned from human bladder cancer cell line [14]. Its presence can be detected by microarray (gene) or immunehistochemistry (protein) a.
Lung Cancer: DSC3 is not seen in normal lung tissue [15]. DSC-3 gene is over expressed 58 fold compared to adenocarcinoma [16]. Immunohistochemistry reveals in lung cancer expression of DSC3 is seen at basal layers of tumor. DSC3 expression is seen in around 30% of cases [17]. DSC 3 expression is seen in squamous NSCLC and not in adenocarcinoma of lung. It is closely associated with p63 expression which is another marker used for differentiation of Squamous NSCLC from other varieties [18][19][20].

b.
OvarianCancer: DSC3 is seen in around 85% of ovarian caners. Its expression seems to be dependent on FSH.

d.
Colorectal Cancer: DSC3 expression is seen in 60% colon cancer and also seen in 40% of colorectal lesion metastatic to the liver [10,25,26].

e.
Bladder Cancer: DSC3 was first cloned from a bladder cancer cell line [14]. We have documented DSC3 expression in around 60% of bladder cancer irrespective of grade and stage of tumor.

h.
Pediatric Acute Lymphoblastic Leukemia: DSC3 gene is described to be over expressed in all TEL-AML1 subtype of paediatric acute lymphoblastic leukemia [29].

i.
Skin Tumors: Loss of DSC3 is seen with tumour development and progression [30] and is associated with increase in K-Ras induced skin tumors [31].

j.
Oral squamous cell carcinoma: Oral mucosa normally expresses DSC3. However development of oral Squamous cell carcinoma is associated with reduction or absence of DSC3 expression. This reduction/absence of DSC3 expression was associated with higher histological grade (moderately or poorly differentiated) [32].

k.
Breastcancer: DSC3 is expressed in a normal breast but is down-regulated in breast cancer cell lines and primary breast tumors at protein as well as gene level [3,33]. The loss of DSC3protein expression is more likely to be aberrant methylation of rather than gene deletion or gross rearrangement of the gene [3].

l.
Prostatecancer: DSC3 is expressed in normalprostate as well asbenign prostate tumors but is absent in prostate cancer due to hyper methylation [34].

Desmocollin-3 as a diagnostic biomarker:
a. Squamous NSCLC: DSC3 is used as a diagnostic biomarker to differentiate Squamous NSCLC from adenocarcinoma of lung [35][36][37][38][39][40][41][42]. DSC3 is more specific for squamous NSCLC compared to p63 as p63 is also expressed in Adenocarcinoma. DSC3 gene is up-regulated in squamous NSCLC and down regulated in adenocarcinoma [43]. Specificity of DSC3 is 100% while sensitivity is variable [18-20, 44,45] and varies with differentiation of tumor. Maximum sensitivity is seen in highly differentiated tumors and is lowest for poorly differentiated Squamous NSCLC. Sensitivity of DSC3 for squamous NSCLC is 93.2% in large cohort of 426 but drops to 59% in poorly differentiated squamous NSCLC (Table 1). DSC3 expression in NSCLC is also not related to stage or histologic grade [17] of a disease [46].

b.
Paediatric Acute Lymphoblastic Leukaemia: DSC3 gene expression can be used to differentiate TEL-AML1 from other subtypes of paediatricacute lymphoblastic leukaemia [29].

Desmocollin-3 as a prognostic biomarker
a) NSCLC: In spite of squamous NSCLC having poor prognosis,smaller clinical trials suggest that DSC3 expressing tumors are likely to have better survival compared to DSC3 negative tumors and may serve as a potential prognostic marker [1,17]. age, gender, size of tumor, tumor grading, and tumor stage in these patients [10]. c) Prostatecancer: Loss of DSC3 predicts poor prognosis.

Effect of therapeutic intervention on DSC3 expression:
a. DNA damaging agents: Expression of wild type of p53 can also be increased or induced by DNA damaging agents like radiotherapy, doxorubicin, cisplatin, paclitaxel, gemcitabine etc. Expressionof wild type p53 is sufficient to induce expression of DSC3 in breast, colorectal and lung cancers in absence of DSC3 DNA methylation [1,10,11]. Expression of wild typep53 converts DSC3 negative tumors in to DSC3 positive.

b.
Tyrosine Kinase inhibitors: DSC3 expression has reciprocal relationship with ERK of MAPK family.Decreased ERK is seen following successful treatment with tyrosine kinase inhibitors. EGFR inhibitor like gefitinib converts DSC3 negative EGFR mutant adenocarcinoma of lung in to DSC3 positive.

Desmocollin-3 and immunotherapy:
DSC3 is a homophilic adhesion molecule, which works as a receptor as well as a ligand. This provides an opportunity to develop an active immunotherapy for DSC3 expressing tumors by inducing DSC3 on surface of tumor targeting activated immune cells. CADI-05 is one such active immunotherapy. It induces DSC3 expression on immune cells and also induces Th1 type of immune response through TLR2 agonist activity [48]. Cadi-05 increases tumor infiltrating immune cells [49] and found useful in management of cancers as a monotherapy for small size tumors [49,50]. As combination therapy with checkpoint modulators, radiotherapy as well as chemotherapy, Cadi-05 improves outcome of large size tumors [51].
Cadi-05 achieves and maintains remission in melanoma as well as in bladder cancer as a systemic monotherapy [52,53]. In combination with chemotherapy, it improves response rate. Responses achieved are durable and results in improved survival. Identical results are seen when combined with radiotherapy. It is expected that combination with anti PD-L1 therapy will result in significant improvement in no. of durable responses.