Pancreatic cancer occurs when some cells , in most cases in the section of the head (about 70%) , multiply out of control. Tumor cells that grow in the pancreas spread easily to nearby lymph nodes and other organs such as the lungs and liver, or can spread into the abdomen, giving rise to the so-called "peritoneal carcinoma". This kind of cancer is asymptomatic until it has reached considerable size or when obstructs major vessels. This, according to the position and relations of the pancreas with the other organs of the abdomen, making pancreatic cancer one of the most difficult forms of cancer to treat.
Pancreas' tumors are still considered as b-killers because the 5-year survival is only about 5% , this is due to the fact that in most cases they are diagnosed in the late phase; in fact 50 of cancers diagnosed is already in a metastatic stage and less than 30 are locally advanced, so not likely to surgery. Pancreatic cancer in an early stage gives no particular signs and symptoms are rather vague, which may be interpreted incorrectly by both patients and doctors. For these reasons, the diagnosis is often made when the disease is already widespread and therefore *only a small percentage of patients is candidabile of surgery.
Today, scientists may have found a solution for diagnosis problems, thanks to the mesothelin. This glycoprotein, overexpressed in pancreatic cancer, could be exploited to perform fast and accurate diagnosis, which is starting to catch on with the Andraka's test.
Symptoms (variable depending on the area of the pancreas where cancer began) appear when the tumor has begun to spread to nearby organs or blocked bile ducts.
They can manifest:
- loss of weight and appetite,
- jaundice (yellowing of the skin),
- pain in the upper abdomen or back,
- nausea or vomit.
- Finally, the percentage of patients ranging from ten to twenty percent may be also affected by diabetes, due to the inability of diseased cells to produce insulin.
When there is suspicion of a tumor of the pancreas can be done several tests to determine whether the doubt is well founded.
How to detect the disease: from the traditional test to the Andraka's method
Imaging currently has made great progress , spiral CAT and magnetic resonance imaging , may be supplemented by an endoscopic technique ( retrograde cholangiopancreatography ) , allow you to define adequately the disease and to provide the surgeon the ability to intervene when there is the criteria of radicality .
Among imaging studies:
- the gold standard for detecting the disease is spiral CAT of the abdomen (also useful because it allows to detect the possible involvement of the great vessels , proved to be more effective than magnetic resonance imaging).
- Ultrasonography is useful in the diagnosis of first level or to detect liver metastases while the laparoscopic biopsy confirms the diagnosis.
- ERCP and EUS are useful to show the involvement of the bile and pancreatic ducts and in the palliative therapy.
The tumor marker CA 19-9 ( carbohydrate antigen 19.9 ) is a sign very sensitive (although not specific ) that is found in very high levels in patients suffering from pancreatic cancer. It is normally used to monitor the evolution of the disease.
The more modern forms of CAT are able to detect tumors of the pancreas, liver and bile ducts .
In the presence of jaundice (yellowing of the skin) is necessary to check if the bile ducts are blocked and if the obstruction is due to a tumor. To do this you can use three different tests:
- the endoscopic retrograde cholangiopancreatography (ERCP ),
- percutaneous transhepatic cholangiography
- magnetic colangiorisonance.
The latter is the least invasive of the three and allows to obtain a good definition of the obstruction site; however does not allow to perform a biopsy to look for the presence of cancer cells, which is instead possible with both other methods.
The patients of pancreatic cancer, also sometimes have increased levels of a protein called CA 19- 9, which, however, is not always present and may be high even in the presence of other diseases. For this reason, when it detects an abnormal value of CA 19- 9 is good to investigate further .
Today we are going to study two new methods of analysis more efficient:
- the study of cancer genes
- the presence of mesothelin.
If the former is more complex, the second has reached with Andraka high levels of operability, proving to be a simple diagnostic test to perform and quite indicative. Let's see what the mesothelin is.
Mesothelin is a glycoprotein expressed in physiological conditions at the level of the mesothelial cells of body serous (pleura, pericardium and peritoneum). The same is, however, overexpressed on the cell surface in many different types of cancer:
- malignant mesothelioma,
- pancreatic and
- lung cancer.
The physiological function of mesothelin is unknown, but it has recently been suggested a role in the mechanisms of cell adhesion by binding to CA125.
The limited expression of mesothelin as regards of physiological tissue and over against the high expression in many tumors, make mesothelin a possible target for anti-tumor therapy.
The biological functions of mesothelin remain largely unknown as mesothelin knockout mice do not show a detectable phenotype . It has been suggested that mesothelin plays a role in tumor adhesion and metastasis based on evidence that it can bind to MUC16 (also known as CA125), which is highly glycosylated, with both O-linked and N-linked oligosaccharides, to mediate heterotypic cell adhesion.studies provide evidence that inhibiting the mesothelin-MUC16 interaction could be a new therapeutic strategy for ovarian cancer and other cancers.
Different type and monoclonal antibodies
There are three type of mesothelin (fig. below).
The mesothelin cDNA and protein were identified using the K1 monoclonal antibody (mAb) generated by the immunization of mice with human ovarian carcinoma (OVCAR-3 cells).
has been identified a monoclonal antibody, OV569, which recognizes mesothelin bound to the surface of the cells of mesothelioma. This antibody also recognizes other soluble molecules that are related to the family of proteins mesothelin.
Correaltion among mesothelin and tumor
we discuss the role of mesothelin in cancer progression and provide new insights into mesothelin-targeted cancer therapy. Recent studies highlight three mechanisms by which mesothelin plays a role in cancer progression. First, mesothelin may aid in the peritoneal implantation and metastasis of tumors through its interaction with mucin MUC16 (also known as CA125). Second, mesothelin may promote cancer cell survival and proliferation via the NF-κB signaling pathway. Finally, mesothelin expression promotes resistance to certain chemotherapy drugs such as TNF-α, paclitaxel, and a combination of platinum and cyclophosphamide. However, its cancer-specific expression makes mesothelin a potential target for monoclonal antibody therapy. New human monoclonal antibodies targeting mesothelin have been isolated by phage display technology and may provide opportunities for novel cancer therapy.
Structure of mesothelin
While the three dimensional structure of mesothelin has not been solved, a recent study predicted both the secondary and three dimensional structures of both mesothelin precursor and mature mesothelin. Nine secondary structure prediction programs predict that both the mesothelin precursor and mature mesothelin are predominantly of helical structure, which is composed of small helical segments separated by short non-helical regions. Based on this secondary structure prediction, four three-dimensional structure prediction programs provide the same type of structure for the mesothelin precursor: a superhelical structure with ARM-type repeats. The model also predicts that the conformation of mature mesothelin may not change after cleavage into its mature form. Interestingly, the structure model for mesothelin is made of tandem repeats of approximately 50 residue-long helix-turn-helix motifs. However, the structure of mesothelin remains unknown.
Role of mesothelin in cancer progression
IL-6 is related to cancer cell survival/proliferation and tumor progression. Overexpression of mesothelin in pancreatic cancer cells led to higher IL-6 production by constitutively activating NF-κB. Conversely, silencing mesothelin reduced levels of IL-6. In pancreatic cells with mesothelin overexpression, high IL-6 may be responsible for triggering the transcription protein 3 (Stat3), resulting in higher expression levels of the cyclin E/cyclin-dependent kinase (CDK2) complex, as well as speeding the G1-S transition. High levels of IL-6 production could up-regulate the soluble IL-6 receptor to stimulate cell proliferation under serum-reduced conditions via an IL-6/sIL-6R (soluble IL-6 receptor) trans-signaling pathway. Even in serum-free medium, cancer cells with forced mesothelin expression grow faster than control cells by producing higher quantities of IL-6. In this case, IL-6 may act as a growth factor to support cancer cell survival. In addition, activation of NF-κB and Stat3 induces expression of Bcl-xl and Bcl-2 and inhibits apoptosis signaling.
Another mechanism may involve the PI3K/Akt pathway to protect cancer cells from drug-induced apoptosis. Mesothelin protects cancer cells from TNF-α induced apoptosis by rapidly stimulating Akt phosphorylation under PI3K activation, inhibiting the expression of pro-apoptotic factors, such as Bad and Bax, and promoting the expression of anti-apoptotic genes.
Some studies found that mesothelin could confer resistance to cytotoxic drug-induced apoptosis. In a human breast cancer model, mesothelin induces anchorage-independent growth and down-regulates the pro-apoptotic protein Bim to confer cancer cell resistance to anoikis-induced apoptosis via stimulation of the ERK signaling pathway. Chemoresistant patients showed significantly higher mesothelin expression than chemosensitive patients.
Collectively, these studies signify the potential role of mesothelin in cancer cell proliferation and indicate that a drug neutralizing the functionality of mesothelin may be useful for novel cancer therapy. Further studies will reveal the role of mesothelin in tumor progression.
Gene regulation of mesothelin in cancer cells
Recently a promoter of mesothelin called Canscript was identified in highly expressing cancer cells, which may contribute to the highly cancer-specific overexpression of mesothelin. The activity of Canscript was increased over 100-fold in cancer cells. The Canscript promoter consists of two motifs: a conventional MCAT motif and a SP1-like motif. Single nucleotide transitional substitution survey confirmed that all eight nucleotides in MCAT are essential for its function. However, the SP1-like element has two point mutations compared to the conserved SP1 motif and binding of an unknown transcription factor to the SP1-like motif may be responsible for cancer-specific expression of mesothelin. Several transcriptional factors such as KLF6 and YAP1 have been investigated. The expression patterns of these transcription factors are consistent with the mesothelin expression pattern in various cell lines but are not sufficient for mesothelin overexpression. The key transcriptional factor which regulates cancer-specific overexpression of mesothelin has not been found.
Mesothelin-based antibody therapy for human malignancies
Mesothelin has been suggested as an attractive target for immunotherapy. Several therapeutic agents that target cell surface mesothelin have been developed and some are being evaluated in preclinical and clinical studies. Recombinant immunotoxin SS1P is composed of a variable fragment (Fv) of SS1 and a truncated form of Pseudomonas exotoxin A (PE). Two phase:
- I clinical trials of SS1P were completed at the U.S. National Cancer Institute (NCI). Based on phase I clinical studies showing the safety of SS1P and its anti-tumor activity, a clinical trial of SS1P in combination with chemotherapy is currently ongoing. MORAb-009 (amatuximab), a chimeric (mouse/human) antibody containing murine SS1 Fv and human IgGγ1 and k constant regions, was developed. A phase I clinical trial of MORAb-009 for mesothelioma, pancreatic cancer and ovarian cancer patients was recently completed. A total of 24 subjects were treated, including 13 mesothelioma, 7 pancreatic cancer, and 4 ovarian cancer patients. Eleven subjects had stable disease.
- Phase II studies of MORAb-009 in different mesothelin-expressing cancers are ongoing.
With two antibodies currently undergoing clinical trials, new antibodies are being investigated as potential therapeutic agents.
Mesothelin has a key role in promoting tumor
Although mesothelin is an attractive therapeutic target and antibody drugs targeting mesothelin are currently being evaluated in clinical trials, the role of mesothelin in cancer progression remains poorly understood. Recent studies have revealed oncogenic functions of mesothelin in cancer survival/proliferation and drug resistance through Wnt/NF-κB/PI3K/Akt signaling pathways. Activity at the Canscript promoter may play a role in the cancer-specific expression of mesothelin. More studies are needed to validate and further investigate the potential role of mesothelin in tumor metastasis, cancer cell survival and proliferation, and drug resistance. The mechanistic studies on mesothelin biology may provide important insights and opportunities for more effective antibody therapy targeting mesothelin in solid tumors.
Mesothelin is expressed in various types of malignant tumors, and it is recently reported that the expression of mesothelin was related to unfavorable patient outcome in pancreatic ductal adenocarcinoma and gastric adenocarcinoma. The expression levels of mesothelin in tumor cells was classified into the localization of mesothelin in luminal membrane and/or cytoplasm, in addition to high and low according to the staining intensity and proportion as a conventional analysis. 'High-level expression' of mesothelin (47.5%) was statistically correlated with liver metastasis (P=0.013) and poorer patient outcome (P=0.022), while 'luminal membrane positive' of mesothelin (52.5%) was more significantly correlated with liver metastasis (P=0.006), peritoneal metastasis (P=0.024) and unfavorable patient outcome (P=0.017). Moreover, it was found that 'cytoplasmic expression' isolated from 'luminal membrane negative' of mesothelin represented the best patient prognosis. It was suggested the pivotal role of mesothelin in cancer promotion depending on its intracellular localization.
When cancer takes hold , the body releases a powerful signal of distress: an overabundance of a protein called mesothelin. The problem is that scientists have not yet developed an easy way to search for molecules of this protein during a standard physical exam or blood test.
This is exactly what might have invented Andraka: a small probe that uses only one-sixth of a drop of blood , which seems to be much more accurate than existing approaches and it only takes five minutes to learn the outcome . It is still preliminary , but pharmaceutical companies are concerned.
It’s builded a network of nanotubes with antibodies specific for mesothelin, and then introduce a drop of blood of a patient with pancreatic cancer. The antibodies bind to mesothelin and increase in size. These molecules strengthened reject nanotubes, changing the electrical properties of the network: the more is mesothelin , the more antibodies bind to the antigen , the more increase in size and the electric signal becomes weaker .
In the light of studies on mesothelin and the test designed by Jack Andraka, now you can run a diagnostic test for pancreatic cancer in a short time and in an effective manner, thus reducing the impact of this disease. This is a big step forward for research against cancer, especially because you can readjust the Andraka's test to other diseases, it would be enough to change the antibodies for mesothelin with those of another type related to another disease.
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Fabio Forino/ Andrea D'Alessio