Pancreatic adenocarcinoma

The digestive system encompasses several organs in which tumors occur with an elevated prevalence and mortality worldwide. Increasing evidence shows that cancer stem cells (CSCs) may play a critical role in tumor development and progression. In addition, CSCs are characterized by resistance to conventional therapies probably explaining why is difficult to completely eradicate cancer. Thus, the research on CSCs is critical to develop therapeutic strategies for a more effective reduction in the risk of relapse and metastasis and possible total elimination of tumors. This review compiles information about markers, signaling pathways and putative targeting of CSCs in several organs of the digestive system in order to unravel common and divergent patterns and behaviors that could be useful for future CSC research.

Pancreatic cancer is one of the most lethal cancer. Developing early screening tools can help in diagnosing pancreatic cancer at earlier stages when surgical resection is still a possibility leading to more years of survival and a potential cure. Here a review is presented about CA 19-9 and some other pancreatic adenocarcinoma serum tumor markers including THBS2, MIC-1, sTRA, CEACAM1, CA 494, Span-1, and PAM4 that show some improvement over CA19-9. A combination of these serum markers in screening tests may yield more sensitive and specific results that can be used for screening high risk as well as the general population. The effectiveness of chemotherapeutic drugs is limited in pancreatic cancer. There is a likelihood that the combination of standard chemotherapy with natural compounds having anti-cancer potential like curcumin will increase the effectiveness of treatment as well as reduce the toxic side effects of standard chemotherapeutic agents. Another review is presented about the potential use of curcumin with standard chemotherapy in pancreatic cancer to increase median survival in pancreatic cancer in comparatively less toxic, novel ways.

Pancreatic cancer is one of the most lethal cancer and there is innate resistance to standard chemotherapy regimens in pancreatic cancer. Gemcitabine was approved in 1996 for the chemotherapeutic treatment of metastatic pancreatic cancer. FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) and gemcitabine plus nab-paclitaxel combination therapies have shown superiority to gemcitabine monotherapy but are more toxic than gemcitabine monotherapy. Therefore, gemcitabine monotherapy is still one of the standard treatments for pancreatic cancer for patients who can't tolerate the toxicity of other chemotherapeutic regimens. The effectiveness of standard chemotherapeutic drugs is limited in pancreatic cancer due to drug resistance, and undesirable side effects. There is a likelihood that the combination of standard chemotherapy with natural compounds having anti-cancer potential like curcumin will increase the effectiveness of treatment as well as reduce the toxic side effects of standard chemotherapeutic agents. Curcumin is a polyphenolic compound isolated from the rhizome of Curcuma longa (turmeric) and is considered a promising anticancer agent. Here, a review is presented about the potential use of curcumin with standard chemotherapy in pancreatic cancer as there is a potential in different combination regimens of curcumin in pancreatic cancer to increase median survival in pancreatic cancer in comparatively less toxic, novel ways. Also, curcumin combination chemotherapy may lead to the improvement of cancer and chemotherapy-related symptoms. The poor bioavailability of curcumin has been the major obstacle for its clinical application. To overcome this problem, several curcumin preparations have been developed including cost-effective preparation methods to increase the bioavailability of curcumin. Different studies have shown that gemcitabine curcumin combination regimen can effectively increase survival with less toxicity in patients who are resistant to gemcitabine and can't even tolerate the toxicity of other chemotherapeutic combination regimens. Although clinical trials are needed, Paclitaxel and curcumin cobound albumin nanoparticles also have the potential to become another alternative chemotherapeutic regimen for pancreatic cancer. For those patients who can tolerate gemcitabine paclitaxel regimen toxicity, there can also be a future possibility of using paclitaxel and curcumin cobound albumin nanoparticles with gemcitabine and this triple therapy may have enhanced therapeutic effects with comparatively less toxic effects. Curcumin has shown its effectiveness with the constituents of FOLFIRINOX in other types of cancers, therefore there is a need for curcumin FOLFIRINOX combined clinical trials in pancreatic cancer as curcumin has the potential to increase the effectiveness of FOLFIRINOX as well as reduce its toxic side effects.

Cystic Fibrosis (CF) is one of the most commonly inherited genetic disorders which will show either asymptomatic features or it prone to severe multiorgan failure and sometimes it may turn into neoplasm and finally death if untreated. CF may hit more than 2000 genes in the human being, but of those ΔF508 mutation in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is the most common one. The leading cause of death in CF patients is due to the involvement of lung and pancreas (pancreatic insufficiency). Even though the primary organ involved in CF is lung, but pancreatic involvement also relates with some important clinical manifestations like diarrhea, steatorrhea, malabsorption, hypovitaminosis, Cystic Fibrosis Related Diabetes (CFRD), pancreatic adenocarcinoma etc., seen in these patients, which is helpful for the physicians to make proper diagnosis and treatment. So, this review article purely focuses on CF especially in relation with pancreatic abnormalities which will be discussed under genetics, pathophysiology (both exocrine and endocrine), cancer, diagnosis and finally treatment.

BACKGROUND
Recent evidences have shown a relationship between prion protein (PrPc) expression and pancreatic ductal adenocarcinoma (PDAC). Indeed, PrPc could be one of the markers explaining the aggressiveness of this tumor. However, studies investigating the specific compartmentalization of increased PrPc expression within PDAC cells are lacking, as well as a correlation between ultrastructural evidence, ultrastructural morphometry of PrPc protein and clinical data. These data, as well as the quantitative stoichiometry of this protein detected by immuno-gold, provide a significant advancement in understanding the biology of disease and the outcome of surgical resection.

AIM
To analyze quantitative stoichiometry and compartmentalization of PrPc in PDAC cells and to correlate its presence with prognostic data

METHODS
Between June 2018 and December 2020, samples from pancreatic tissues of 45 patients treated with pancreatic resection for a preoperative suspicion of PDAC at our Institution were collected. When the frozen section excluded a PDAC diagnosis, or the nodules were too small for adequate sampling, patients were ruled out from the present study. Western blotting was used to detect, quantify and compare the expression of PrPc in PDAC and control tissues, such as those of non-affected neighboring pancreatic tissue of the same patient. To quantify the increase of PrPc and to detect the subcellular compartmentalization of PrPc within PDAC cells, immuno-gold stoichiometry within specific cell compartments was analyzed with electron microscopy. Finally, an analysis of quantitative PrPc expression according to prognostic data, such as cancer stage, recurrence of the disease at 12 mo after surgery and recurrence during adjuvant chemotherapy was made.

RESULTS
The amount of PrPc within specimen from 38 out of 45 patients was determined by semi-quantitative analysis by using Western blotting, which indicates that PrPc increases almost three-fold in tumor pancreatic tissue compared with healthy pancreatic regions [242.41 ± 28.36 optical density (OD) vs 95 ± 17.40 OD, P < 0.0001]. Quantitative morphometry carried out by using immuno-gold detection at transmission electron microscopy confirms an increased PrPc expression in PDAC ductal cells of all patients and allows to detect a specific compartmentalization of PrPc within tumor cells. In particular, the number of immuno-gold particles of PrPc was significantly higher in PDAC cells respect to controls, when considering the whole cell (19.8 ± 0.79 particles vs 9.44 ± 0.45, P < 0.0001). Remarkably, considering PDAC cells, the increase of PrPc was higher in the nucleus than cytosol of tumor cells, which indicates a shift in PrPc compartmentalization within tumor cells. In fact, the increase of immuno-gold within nuclear compartment exceeds at large the augment of PrPc which was detected in the cytosol (nucleus: 12.88 ± 0.59 particles vs 5.12 ± 0.32, P < 0.0001; cytosol: 7.74. ± 0.44 particles vs 4.3 ± 0.24, P < 0.0001).

In order to analyze the prognostic impact of PrPc, we found a correlation between PrPc expression and cancer stage according to pathology results, with a significantly higher expression of PrPc for advanced stages. Moreover, 24 patients with a mean follow-up of 16.8 mo were considered. Immuno-blot analysis revealed a significantly higher expression of PrPc in patients with disease recurrence at 12 mo after radical surgery (360.71 ± 69.01 OD vs 170.23 ± 23.06 OD, P = 0.023), also in the subgroup of patients treated with adjuvant CT (368.36 ± 79.26 OD in the recurrence group vs 162.86 ± 24.16 OD, P = 0.028), which indicates a correlation with a higher chemo-resistance.

CONCLUSION
Expression of PrPc is significantly higher in PDAC cells compared with control, with the protein mainly placed in the nucleus. Preliminary clinical data confirm the correlation with a poorer prognosis.

Pancreatic adenocarcinoma is not the most frequent cancer, but it is one of the deadliest cancers. The 5-year survival rate is 9% only. It is usually diagnosed at a later stage when surgical resection is not possible and metastases have already spread to other parts of the body. Developing early screening tools can help in diagnosing pancreatic cancer at initial and earlier stages when surgical resection is still a possibility leading to more years of survival and a potential cure. Different studies show the importance of identification of pancreatic carcinoma before large growth in tumor size. Recurrence after surgery is late if serum tumor marker level is comparatively less, tumor size is small and it is localized with no lymph node or vascular invasion and so according to different studies, early detection of tumor lead to more median survival time. There are many pancreatic carcinoma serum tumor markers, but most of them do not improve upon CA19-9 which is considered a gold standard pancreatic carcinoma serum marker although CA 19-9 also does not have perfect sensitivity and specificity. Because of less than 100% sensitivity and specificity, screening tests, using serum markers are mostly not recommended for the general population, although they are recommended for high-risk populations. Here we present a brief review about Ca 19-9 and some other pancreatic adenocarcinoma serum tumor markers including THBS2, MIC-1, sTRA, CEACAM1, CA 494, Span-1 and PAM4 which show some improvement over CA19-9. CA 19-9 is considered the standard pancreatic adenocarcinoma serum tumor marker but there are other pancreatic adenocarcinoma serum tumor markers with comparatively better sensitivity and specificity. THBS2 has comparatively less sensitivity but better specificity compared to CA 19-9. PAM4 has comparatively less or equal sensitivity but better specificity compared to CA 19-9. CEACAM1 and CA 494 have comparatively better sensitivity and specificity compared to CA 19-9. Span-1 has comparatively better sensitivity but less or equal specificity compared to CA19-9. MIC-1 has comparatively better sensitivity but less specificity compared to CA 19-9. sTRA has comparatively better sensitivity and equal specificity, also it is secreted by pancreatic adenocarcinoma cells which are different from those which secrete CA19-9. There is a possibility that a combination of these serum markers in screening tests may yield more sensitive and specific results that can be used for screening high risk as well as the general population.