Materiały źródłowe

• #1 KEGG DISEASE: Gallbladder cancer

  https://www.genome.jp/dbget-bin/www_bget?ds:H00047

  Gallbladder cancer (GBC) is a relatively uncommon neoplasm, however its prognosis is poor with less than a 5% 5-year survival rate. […] Two main pathways of GBC pathogenesis have been identified. The most common is associated with gallstones and chronic inflammation of the gallbladder, whereas a second, less frequent pathway is associated with a congenital abnormality of the pancreatic bile-duct junction, which is particularly common in Japan. TP53 inactivation has an important and early role in GBC associated with gallstones and chronic inflammation. Although KRAS mutations are rarely detected in GBC associated with gallstones, they are frequent and early events in tumors associated with congenital abnormality of the pancreatic bile-duct junction.

• #2 Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update

  https://www.wjgnet.com/1007-9327/full/v23/i22/3978.htm

  Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. […] The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. […] An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. […] The development of gallbladder cancer has been linked to various genetic and environmental factors. Chronic infection of gallbladder or/and environmental exposure to specific chemicals, heavy metals, and even many dietary factors, have been found to be associated with GBC formation. […] The dramatic association of GBC with female gender and certain geographical regions (mostly developing countries) has been proposed to be influenced by various female hormones, cholesterol cycling and salmonella infections in existing literature.

• #3 Gallbladder cancer: lessons from a rare tumour – SEARCH

  https://primo.qatar-weill.cornell.edu/discovery/fulldisplay/cdi_proquest_miscellaneous_66836340/974WCMCIQ_INST:VU1

  Key Points Gallbladder cancer is a relatively rare neoplasm worldwide, but shows significant geographic variation in incidence, being particularly common in certain native American populations. The prognosis for patients with this neoplasm is poor, as diagnosis is often at late, untreatable stages of the disease. A unique combination of predisposing factors makes gallbladder carcinoma a unique tumour and offers potential for understanding cancer pathogenesis. These factors include ethnicity, genetic predisposition, geographic location, female gender, chronic inflammation and congenital developmental abnormalities. Two main pathways of gallbladder carcinoma pathogenesis have been identified. The most common is associated with gallstones and chronic inflammation of the gallbladder, whereas a second, less frequent pathway is associated with a congenital abnormality of the pancreatic bile-duct junction, which is particularly common in Japan. A multistage sequence of histopathological and molecular changes has been identified for gallbladder carcinoma, which is especially well-defined for tumorigenesis associated with gallstones. Molecular abnormalities commence in normal-appearing epithelium in chronically inflamed gallbladders. TP53 inactivation has an important and early role in gallbladder carcinoma associated with gallstones and chronic inflammation. Different patterns of TP53 mutation have been detected in the two main types of gallbladder carcinomas that have been identified. Although KRAS mutations are rarely detected in gallbladder carcinomas associated with gallstones, they are frequent and early events in tumours associated with congenital abnormality of the pancreatic bile-duct junction. Relatively little is known about gallbladder cancer, and a significant influx of research funding is required for this to be remedied. In particular, the identification of susceptibility genes, elucidation of the role of inflammation and an increased understanding of the molecular changes that occur during multistage pathogenesis should be important goals for the future.

• #4 Gallbladder cancer: review of a rare orphan gastrointestinal cancer with a focus on populations of New Mexico | BMC Cancer | Full Text

  https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4575-3

  Gallbladder cancer is a rare malignancy of the biliary tract with a poor prognosis, frequently presenting at an advanced stage. […] Similar to other gastrointestinal cancers, gallbladder cancer etiology is likely multi-factorial involving a combination of genomic, immunological, and environmental factors. Understanding the interplay of these unique epidemiological factors is crucial in improving the prevention, early detection, and treatment of this lethal disease. […] Examples include, interest in the HER2/Neu signaling pathway and the recognition that chronic inflammation plays a crucial role in gallbladder cancer pathogenesis. […] A better understanding of GBC pathogenesis is urgently needed to develop targeted therapy approaches to improve outcomes in GBC patients. […] Chronic inflammation of the gallbladder may be due to pre-existing gallstones or infections (e.g., Salmonella).

• #5 Gallbladder Cancer | IntechOpen

  https://www.intechopen.com/chapters/1145835

  Gallbladder cancer is a rare and highly aggressive malignancy that presents significant challenges for diagnosis and treatment. […] Gallbladder cancer is often asymptomatic in its early stages, making it difficult to detect and diagnose. Additionally, there are several risk factors associated with gallbladder cancer, including gallstones, chronic inflammation, obesity, and genetic factors, which further complicate the diagnostic process. […] Gallstones, along with the associated cholecystitis, lead to a sequence of events that result in dysplasia and eventually carcinoma of the gallbladder in over 90% of cases. […] Two patterns of malignant transformation have been observed in the gallbladder: the metaplasia-dysplasia-carcinoma sequence and the adenoma-carcinoma sequence. However, carcinogenesis related to biliary lithiasis primarily occurs through the metaplasia-dysplasia-carcinoma pathway, rather than transformation from a pre-existing benign tumor lesion.

• #6 Comprehensive single-cell analysis deciphered microenvironmental dynamics and immune regulator olfactomedin 4 in pathogenesis of gallbladder cancer | Gut

  https://gut.bmj.com/content/73/9/1529

  Objective Elucidating complex ecosystems and molecular features of gallbladder cancer (GBC) and benign gallbladder diseases is pivotal to proactive cancer prevention and optimal therapeutic intervention. […] The pathogenesis of GBC often follows metaplasia-dysplasia-carcinoma or adenoma-carcinoma sequence. […] Persistent inflammation exists in both pathogenic ways and plays a pivotal role in driving the tumourigenesis of GBC, regardless of its lithogenic or non-lithogenic origin. […] The advances in omics technologies have provided novel insights into the mutational landscape, molecular characteristics and dysregulation of signalling pathways, leading to the emergence of several therapeutic targets, such as HER2, VEGFR and PD-(L)1. […] Our study identified elevated olfactomedin 4 (OLFM4) in epithelial cells as a central player in GBC progression. OLFM4 was related to T-cell malfunction and tumour-associated macrophage infiltration, leading to a worse prognosis in GBC.

• #7 Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5473118/

  The serious of genetic alteration leading to gallbladder cancer formation is still not established clearly. […] Gallbladder carcinoma develops through a serious of events before converting in to invasive malignancy. Any exposure to carcinogens may convert normal gallbladder epithelium to condition called metaplasia which subsequently forms dysplasia to carcinoma in situ (CIS), and finally proceeding to invasive carcinoma in about 15 years. […] The multistage pathogenesis of gallbladder carcinoma begins with gallstones giving rise to a condition called chronic cholecystitis, which increases to risk to gallbladder cancer formation.

• #8 Gallbladder cancer pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Gallbladder_cancer_pathophysiology

  In the setting of a chronically inflamed gallbladder, metaplasia is not unusual. […] The definite relationship between metaplasia and dysplasia, is not clearly established yet. […] This concept is supported via the finding that over 80% of invasive gallbladder cancers have adjoining areas of CIS and epithelial dysplasia. […] Dysplastic lesions have molecular genetic proof that supports progression towards CIS. […] It is well recognized that gallbladder dysplasia progresses to invasive most cancers normally over a path of 15 to 19 years. […] There are also histologic and molecular differences in GBCs related to anomalous pancreaticobiliary duct junction and in the ones related to gallstones, providing further proof that two different pathogenetic pathways are involved. […] GBC arising in Japan within the setting of an anomalous pancreaticobiliary duct junction is characterized by means of KRAS mutations and relatively late onset of p53 mutations.

• #9 Pathology Outlines – Gallbladder carcinoma

  https://www.pathologyoutlines.com/topic/gallbladdercarcinoma.html

  Carcinoma arising from the gallbladder epithelium (WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019) […] Longstanding cholelithiasis and cholecystitis give rise to metaplastic changes (intestinal or pseudopyloric types) in the gallbladder mucosa (Cancer 1993;72:1878) […] Metaplasia (especially intestinal type) gives rise to epithelial dysplasia and carcinoma in situ (J Hepatobiliary Pancreat Surg 2000;7:556) […] Progression from dysplasia to advanced gallbladder carcinoma takes around 15 years (Gastroenterology 1996;111:232) […] Risk factors include: Cholelithiasis (major risk factor) […] Chronic cholecystitis, especially hyalinizing cholecystitis […] Obesity […] Infections (especially Salmonella and Opisthorchis viverrini) […] Porcelain gallbladder

• #10 Gallbladder cancer pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Gallbladder_cancer_pathophysiology

  Less than 3% of early gallbladder carcinomas have adenomatous remnants, indicating this mechanism has less importance within the carcinogenic pathway. […] In contrast to properly-established carcinogenic pathways in colorectal most cancers, it remains debated within the literature whether or not or not adenomas are actual precursors of invasive gallbladder carcinomas.

• #11

  https://link.springer.com/article/10.1007/s005340050113

  While considerable progress has been made in the understanding of the genetic changes involved in the pathogenesis of several human neoplasms, there is limited information about the genetic changes involved in the development of gallbladder carcinoma. Several studies indicate that TP53 (17p13) and p16Ink4/CDKN2 (9p21-22) gene loci abnormalities are frequent and early events in the pathogenesis of this neoplasm, in some cases preceding the onset of histological changes of invasion. […] Genetic studies confirm that the sequence dysplasia-carcinoma in situ (CIS) is the usual route for the development of gallbladder carcinoma, and our recent data strongly suggest that adenomas are not precursors of this neoplasm.

• #12 Gallbladder Carcinoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK442002/

  Chronic inflammation is the most common pathogenic pathway associated with gallbladder carcinoma. […] Chronic inflammation is the primary oncogenic driver of gallbladder carcinoma. Toxins and direct injury may be additional pathophysiologic factors. The mutational profile of gallbladder adenocarcinoma most commonly involves K-ras, TP53, CDKN2a, and c-erb-b2 mutations. In addition, gene promoter hypermethylation has been increasingly identified as a pathogenic contributor. In a subset of patients, advancement to cancer may follow a pathway similar to cancer that arises from premalignant lesions in other organs, such as colon cancer (ie, gallbladder adenomas), which progresses from dysplasia to invasive cancers. The heterogeneity in genetic drivers is further evidence of the complex pathogenesis of gallbladder carcinoma.

• #13 Gallbladder Tumors: Practice Essentials, Anatomy, Pathophysiology

  https://emedicine.medscape.com/article/190364-overview

  Chronic inflammation from a variety of stimuli has been implicated in the pathogenesis of gallbladder cancer. […] Numerous studies have investigated genetic abnormalities in gallbladder cancer and have shown that approximately 39-59% of these cancers are associated with the K-ras mutation, whereas more than 90% are associated with a p53 mutation. Other studies have identified higher levels of microsatellite instability and loss of heterozygosity when gallbladder cancers develop against a background of chronic cholecystitis. […] A number of other genetic abnormalities have been associated with gallbladder cancer, including overexpression of the c-erb-2 gene, upregulation of cyclin D1, p16, p27, and MSH2. […] The most common risk factor for gallbladder cancer is gallstones, which are present in 75-90% of gallbladder cancer cases.

• #14 Gallbladder Cancer: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/278641-overview

  Gallbladder cancer typically arises in the setting of chronic inflammation. In the vast majority of patients (75%), the source of this chronic inflammation is cholesterol gallstones. The presence of gallstones increases the risk of gallbladder cancer 4- to 5-fold. […] Other more unusual causes of chronic inflammation are also associated with gallbladder cancer. These causes include primary sclerosing cholangitis, inflammatory bowel disease, liver fluke infestation, chronic Salmonella typhi and paratyphi infections, and Helicobacter infection. […] However, chronic gallbladder inflammation is likely only part of the cause of the malignant transformation seen in gallbladder cancer. Many other factors have been identified. Ingestion of certain medications (eg, oral contraceptives, isoniazid, methyldopa) can increase the risk of gallbladder cancer.

• #15 Gallbladder cancer: review of a rare orphan gastrointestinal cancer with a focus on populations of New Mexico | BMC Cancer | Full Text

  https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4575-3

  Chronic inflammation induced carcinogenesis involves recurrent cycles of epithelial damage and repair. Long-term chronic inflammation results in the sustained release of inflammatory mediators, such as cytokines, chemokines, and prostaglandins into the tissue microenvironment. […] Cytokine induced inflammation may result in activation of oncogenes and inactivation of tumor suppressor genes leading to cell transformation, proliferation, and inhibition of apoptosis. […] The link between innate immunity and GBC is interesting due to the possible key role played by chronic Salmonella infections and GBC in India. […] Chronic inflammation, via various chemokines, can result in somatic mutations linked with carcinogenesis. […] The underlying somatic molecular changes of GBC remain ill-understood. […] The genomic changes in GBC are likely the result of a complex interactions due to the initiating chronic inflammation and environmentally driven factors over a prolonged period.

• #16 Environmental and Lifestyle Risk Factors in the Carcinogenesis of Gallbladder Cancer

  https://www.mdpi.com/2075-4426/12/2/234

  Interestingly, about 15% of cancers—including GBC—are preceded by chronic inflammation, which can be local (e.g., inflammation due to gallstones or infections) or systemic (e.g., metabolic syndrome). Therefore, the inflammatory component of GBC can come from different sources, producing an inflammatory state of a summative nature that provides the ideal niche for carcinogenic progress. […] One of the most studied cytokines that has been linked to cancer is tumor necrosis factor α (TNF-α). It has been shown that cancer cells release TNF-α, promoting cell transformation, tumorigenesis, and metastasis. […] In 1986, Yamagiwa et al. proposed a GBC progression sequence through which a normal mucosa develops metaplasia, then dysplasia and ultimately a carcinoma. […] The main consequence of TP53 alterations is the loss of its function, decreasing its capacity as a tumor suppressor, causing cells to begin to lose regulation of the cell cycle, and perpetuating the successive mutations in DNA that translate into greater genomic instability.

• #17 Gallbladder Tumors: Practice Essentials, Anatomy, Pathophysiology

  https://emedicine.medscape.com/article/190364-overview

  Causality is difficult to establish, but other chronic inflammatory conditions, such as cholecystoenteric fistula, primary sclerosing cholangitis (PSC), pancreaticobiliary maljunction, and chronic infection with Salmonella typhi, have also been associated with an increased risk of gallbladder cancer. […] On the basis of these associations, chronic inflammation is postulated to be involved in the pathogenesis of gallbladder cancer. […] As noted, an adenoma-carcinoma sequence is thought to be involved in many cases of gallbladder cancer. Histologically, adenocarcinoma is found in 90% of gallbladder cancer cases, and squamous cell carcinoma is found in 2% of cases.

• #18 Gallbladder Cancer | IntechOpen

  https://www.intechopen.com/chapters/1145835

  Certain types of infections, likely due to bile and bile salt deconjugation, can also contribute to the development of gallbladder cancer (infection by Salmonella typhi, Clonorchis sinensis, Opisthorchis viverrini, as well as various species of Escherichia, Klebsiella, and Helicobacter). […] Reflux of pancreatic juice into the bile ducts and the gallbladder itself can underlie the development of gallbladder carcinoma, as supported by experimental findings that have shown a higher incidence of this disease in individuals with anomalous drainage of the Wirsung and common bile duct into the duodenum. […] The close association between gallbladder neoplasia and intrahepatic bile duct neoplasms supports the concept of field cancerization in the biliary tract of patients with PSC.

• #19 Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update

  https://www.wjgnet.com/1007-9327/full/v23/i22/3978.htm

  To some extent, the female hormone estrogen causes increased cholesterol super saturation in bile and hence involved in gallstone mediated GBC pathogenesis. […] Although the female gender GBC can be linked with the role of female hormones. […] Other well-known GBC associated risk factors such as porcelain gallbladder, Mirizzis syndrome and bile reflux has also been playing a major role as a predisposing factors of this disease. […] Present data suggest that gallstones are a major risk factor for GBC but their role as a cause for gallbladder cancer is still not certain. […] Convincing evidence also exists for the presence of gallstones as strongly associated factor for gallbladder cancer etiology. […] The present existing information regarding genetic and molecular alterations in GBC is still very much limited. Like other neoplasms, GBC is a multifactorial disorder involving multiple genetic alterations.

• #20 Molecular genetics changes in gallbladder carcinoma – International Journal of Molecular and Immuno Oncology

  https://ijmio.com/molecular-genetics-changes-in-gallbladder-carcinoma/

  GBC is a multi-factorial disease involving numerous genetic changes. In view of the present knowledge, genetic and molecular changes in GBC are still needs to be explored. […] Some common aberrations include the activation of oncogenes, inactivation of tumor suppressor genes (TSGs), presence of microsatellite instability, and epigenetic changes mainly caused by atypical promoter methylation of gene areas are the various common factors reported till now. The serious of genetic changes leading to gallbladder cancer development is still not well known. […] The present article will describe some of the important genetic changes reported in GBC. […] Oncogenes cause alteration in normal cells to transform it into cancerous cells (with abnormal cell growth) is considered as oncogenes. Oncogenes are usually mutated forms of normal cellular genes (proto-oncogenes) that get altered in the gallbladder cancer signaling cascade.

• #21 Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update

  https://www.wjgnet.com/1007-9327/full/v23/i22/3978.htm

  The serious of genetic alteration leading to gallbladder cancer formation is still not established clearly. […] The existing literature has reported mutations of the TP53 gene in between approximately 27% to 70% of gallbladder carcinomas. […] The multistage pathogenesis of gallbladder carcinoma begins with gallstones giving rise to a condition called chronic cholecystitis, which increases to risk to gallbladder cancer formation. […] More than 90% of patients with gallbladder carcinoma show dysplasia and CIS. […] The only two markers i.e., carcino-embryonic antigen (CEA) and carbohydrate antigen 19-9 are most often elevated in advanced stages with a low specificity. […] Various lines of evidence suggest role for various environmental risk factors in Gallbladder carcinoma. […] Despite of many articles regarding genetic predisposition of gallbladder cancer there is no established genetic marker.

• #22 Molecular genetics changes in gallbladder carcinoma – International Journal of Molecular and Immuno Oncology

  https://ijmio.com/molecular-genetics-changes-in-gallbladder-carcinoma/

  Overexpression of HER-2/neu is important for carcinogenesis of gallbladder cancers and helpful for detection of early diagnosis. […] Dysregulation in TP53 gene leads to cancer cell proliferation and immortality. […] Mutations in TP53 gene are reported in a majority of human malignancies and point mutations of the TP53 gene are among the greatest common genetic alterations in human cancers and are supposed to perform a critical role in the pathogenesis of many malignancies including GBC. […] FHIT is a TSG that lost during gallbladder carcinogenesis, which reported on chromosome 3p. […] The loss of FHIT prompts global genome instability, mostly through nucleotide imbalance, spontaneous replication stress, and DNA breaks whereas methylation of the promoter, frameshift mutation, and elevated expression are common in GBC.

• #23 TP53 Abnormalities are frequent and early events in the sequential pathogenesis of gallbladder carcinoma

  https://www.medigraphic.com/cgi-bin/new/resumenI.cgi?IDARTICULO=12576

  TP53 Abnormalities are frequent and early events in the sequential pathogenesis of gallbladder carcinoma. […] The knowledge of the molecular events involved in its pathogenesis is scarce. […] We investigated the role of TP53 inactivation in the sequential pathogenesis of GBC. […] GBCs demonstrated a high frequency of LOH (81%) and mutation (67%), and both abnormalities indicating gene inactivation were detected in 52%. […] These findings indicate that TP53 abnormalities are early and frequent events in the pathogenesis of GBC, starting from chronic cholecystitis.

• #24 Molecular genetics changes in gallbladder carcinoma – International Journal of Molecular and Immuno Oncology

  https://ijmio.com/molecular-genetics-changes-in-gallbladder-carcinoma/

  When a proto-oncogene altered, it becomes a gain of function mutant gene that can become permanently activated and influence cancer formation. […] Many pathogenic mutations have been described in K-ras oncogene in GBC tissue. […] K-ras gene mutations identified in GBC generally affects codons 12, 13, and 61 results in inability to hydrolyze bound guanosine triphosphate and incapability to switch back to the inactive configuration, resultant inappropriate growth signal. […] The identified rates of K-ras mutations were 55-57% for gallbladder cancers. […] GBC connected with an Anomalous Pancreaticobiliary Duct Junction have a high K-ras gene mutation rate in 50-83% of cases and this indicate that the detection of K-ras mutation is a valuable molecular diagnostic marker for GBC in this category of patients.

• #25 KEGG DISEASE: Gallbladder cancer

  https://www.genome.jp/dbget-bin/www_bget?ds:H00047

  Gallbladder cancer (GBC) is a relatively uncommon neoplasm, however its prognosis is poor with less than a 5% 5-year survival rate. […] Two main pathways of GBC pathogenesis have been identified. The most common is associated with gallstones and chronic inflammation of the gallbladder, whereas a second, less frequent pathway is associated with a congenital abnormality of the pancreatic bile-duct junction, which is particularly common in Japan. TP53 inactivation has an important and early role in GBC associated with gallstones and chronic inflammation. Although KRAS mutations are rarely detected in GBC associated with gallstones, they are frequent and early events in tumors associated with congenital abnormality of the pancreatic bile-duct junction.

• #26 Overview of current targeted therapy in gallbladder cancer | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-020-00324-2

  With regards to recently intense clinical research on varied specific agents that intervene intracellular signaling pathways dysfunctional in GBC, here we updated these targeted therapies on individual signaling pathways, including human epidermal growth factor receptor 2 (HER2), growth factor receptor tyrosine kinases (RTKs) (EGFR, vascular endothelial growth factor receptor (VEGFR)), programmed death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1), TP53, KIT, CDKN2A/B, phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), and RAS/BRAF/MEK/MAK. […] Abnormality of HER2 with gene overexpression and/or activated mutations has been reported in multiple cancers, such as breast cancer, colon cancer, lung cancer, stomach cancer, and BTC. […] In human GBC, HER overexpression was found between 9.8 and 12.8%.

• #27 Molecular genetics changes in gallbladder carcinoma – International Journal of Molecular and Immuno Oncology

  https://ijmio.com/molecular-genetics-changes-in-gallbladder-carcinoma/

  EGFR is normally present within the plasma membrane of many types of normal cells, it is commonly over-expressed or over-activated in malignant cells. […] When active, it stimulates intracellular pathways that promote cell proliferation and angiogenesis, in addition to evasion of apoptosis. […] The EGFR mutations, including activating and resistant mutations, frequently occur in exons 18-21 of the EGFR gene encoding the adenosine triphosphate-binding pocket of the intracellular TK domain. […] Somatic mutations of the EGFR tyrosine kinase domain are reported in nearly 15% of the GBC. […] The role of HER family of tyrosine kinases playing an important role in the pathogenesis of cancer is well established. […] The HER2/neu receptors undergo dimerization and transphosphorylation of their intracellular domains, which trans-activate numerous intracellular signaling molecules and adaptor proteins (Shc), which in turn lead to the activation of downstream pathways, such as ras-RAF-MEK ERK1/2 and PI3k-AKT-mTOR resulting in cancer cell proliferation and cell survival.

• #28 Overview of current targeted therapy in gallbladder cancer | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-020-00324-2

  The overexpression population of EGFR in GBC was observed between 44 and 77% of patients in different independent studies. […] Elevated expression of EGFR in GBC tissues was positively correlated with poor prognosis of the patients. […] A number of membrane receptors and intracellular proteins are directly or indirectly able to activate RAS, which includes KRas, HRas, and NRas family members. […] Once the RAS protein is activated, it recruits RAF kinase family members such as Araf, Braf, or Craf to the plasma membrane and elicits downstream MEK. […] There was ample convincing evidence demonstrating that KRAS mutations mediate carcinogenesis of BTC by multiple research groups. […] Accumulating research evidence, not limited to PI3K, AKT, and mTOR, has also unveiled tumor-promoting function of important molecules that manipulate activation of the PI3K/AKT/mTOR pathway.

• #29 Molecular genetics changes in gallbladder carcinoma – International Journal of Molecular and Immuno Oncology

  https://ijmio.com/molecular-genetics-changes-in-gallbladder-carcinoma/

  The expression of E-CDH1 diminishes as the tumor progresses. […] COX-2 expression reported to be reduced in adenocarcinoma (59.2%) when compared with dysplastic epithelium (70.3%). […] It has also been noted that the increased neovascularization induced by COX-2 might be responsible for the poor prognosis of human GBC patients. […] The VEGF-A is a potent proangiogenic agent involved in many types of carcinogenesis and an attractive target for cancer therapy. […] Survivin overexpression is reported during fetal development but low in healthy adult tissues. Overexpression of survivin has been studied in various cancers. Survivin expression was significantly overexpressed in GBC than cholelithiasis. The results from different studies suggested its role in gallbladder carcinogenesis.

• #30 Overview of current targeted therapy in gallbladder cancer | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-020-00324-2

  Supporting the evidence, these activated mutations of HER2/3 in GBC cell lines resulted in a significant increase in cell proliferation and tumor development in animals, underscoring the essential role of HER2/3 mutations in the development of GBC. […] The binding of VEGF to VEGFR2 leads to phosphorylation of VEGFR2 at Tyr951 and Tyr1175, in which phosphorylated Tyr951 regulates vascular permeability mediated by SRC tyrosine kinase activation, whereas phosphorylated Tyr1175 of VEGFR2 recruits phospholipase C (PLC-) and activates downstream of both MAPK cascade and PI3K/AKT pathway, stimulating endothelial cell proliferation and survival. […] It is well appreciated that microvessel density correlated with cancer progression, metastasis, and prognosis in GBC and VEGF-A was overexpressed to serve as an independent prognostic factor of survival in GBC.

• #31 Aging-US: Proliferation, migration, & invasion of pathways: gallbladder cancer | Aging

  https://www.aging-us.com/news-room/proliferation-migration-invasion-of-pathways-gallbladder-cancer

  Melatonin inhibits proliferation, migration, and invasion by inducing ROS-mediated apoptosis via suppression of the PI3K/Akt/mTOR signaling pathway in gallbladder cancer cells. […] However, the effects of melatonin in gallbladder cancer and the related mechanism remain unknown. […] The Shi/Zhai Research Team concluded in their Aging-US Research Output, „the present study demonstrates that melatonin suppresses proliferation, migration, as well as invasion of gallbladder cancer cells. Mechanistically, in vitro, melatonin promoted ROS-mediated apoptosis of gallbladder cancer cells. Further studies suggest that melatonin suppresses the phosphorylation of the PI3K/Akt/mTOR signaling pathway. […] Overall, melatonin may be an effective and novel candidate for the treatment of gallbladder cancer.”

• #32 The Multiple Molecular Signatures in Gallbladder Carcinoma: from Basic Studies to Clinical Application

  http://www.fortunejournals.com/articles/the-multiple-molecular-signatures-in-gallbladder-carcinoma-from-basic-studies-to-clinical-application.html

  Through recent research, long non-coding RNAs also have been determined to play important roles in GBC pathogenesis. Long non-coding RNA SPRY4-IT1 promoted GBC progression and may serve as a candidate target for new therapies in human GBC. […] Indeed, long non-coding RNAs have important interactions with mRNAs and miRNAs. […] Compared with molecules above mentioned, crucial proteins also contribute to diagnosis and treatment of GBC. The modification of proteins, mainly including protein phosphorylation and acetylation, may contribute to abnormal expression and/or function. […] Research on the pathogenesis and prognosis of GBC has made great progress, and genes have been determined to be possible markers for prognosis. Lupeol in the EGFR/MMP-9 pathway was proved to induce apoptotic cell death in GBC, which can be used as a potential treatment method. Long non-coding RNAs of LINC00152 and CRNDE in the PI3K-AKT pathway contribute to process of GBC carcinogenesis, and PI3K/AKT may be a potential therapeutic target for GBC.

• #33

  https://link.springer.com/article/10.1007/s00210-024-03279-1

  Gallbladder cancer (GBC) is an aggressive and lethal malignancy with a poor prognosis. Long noncoding RNAs (lncRNAs) and natural products have emerged as key orchestrators of cancer pathogenesis through widespread dysregulation across GBC transcriptomes. Functional studies have revealed that lncRNAs interact with oncoproteins and tumor suppressors to control proliferation, invasion, metastasis, angiogenesis, stemness, and drug resistance. […] The lncRNAs, i.e., SNHG6, Linc00261, GALM, OIP5-AS1, FOXD2-AS1, MINCR, DGCR5, MEG3, GATA6-AS, TUG1, and DILC, are key players in regulating the aforementioned processes. For example, the lncRNAs FOXD2-AS1, DILC, and HOTAIR activate oncogenes such as DNMT1, Wnt/-catenin, BMI1, and c-Myc, whereas MEG3 and GATA6-AS suppress the tumor proteins NF-B, EZH2, and miR-421.

• #34 Gallbladder Carcinoma : A Comprehensive Review and Recent Updates | IntechOpen

  https://www.intechopen.com/online-first/1219270

  Mutations in the P53 gene are implicated in the development of GBC. Alterations in the NLRP3 gene leading to mutations in Interleukin-10/1, TNF-, and COX-2 genes contribute to the development of GBC. […] Several metals like arsenic, boron, lithium, and molybdenum were implicated in the pathogenesis of gallstone and GBC. Arsenic has a carcinogenic effect due to DNA damage and genomic alterations. […] The apoptosis pathway triggered by TNF-R1 and other death receptors, including TRAIL, FAS, and CD-95, leads to sequential activation of procaspase-8 and Phospholipase A2.

• #35 Gallbladder cancer | World Cancer Research Fund

  https://www.wcrf.org/preventing-cancer/cancer-types/gallbladder-cancer/

  Approximately 9095% of gallbladder cancers are adenocarcinomas, which means the cancer started in gland cells in the gallbladder lining. […] Evidence for what can cause gallbladder cancer comes from large population studies (called epidemiology) and biological studies (where scientists look at cells in a laboratory). […] For scientists: full references, pathogenesis and a summary of the mechanisms underpinning our findings on how to prevent gallbladder cancer can be found in our 2018 gallbladder cancer report. […] We have strong evidence from our research that living with overweight or obesity increases the risk of gallbladder cancer. Other causes, except gallstones, have not been established.

• #36 Environmental and Lifestyle Risk Factors in the Carcinogenesis of Gallbladder Cancer

  https://www.mdpi.com/2075-4426/12/2/234

  Gallbladder cancer (GBC) is an aggressive neoplasm that in an early stage is generally asymptomatic and, in most cases, is diagnosed in advanced stages with a very low life expectancy because there is no curative treatment. Therefore, understanding the early carcinogenic mechanisms of this pathology is crucial to proposing preventive strategies for this cancer. The main risk factor is the presence of gallstones, which are associated with some environmental factors such as a sedentary lifestyle and a high-fat diet. Other risk factors such as autoimmune disorders and bacterial, parasitic and fungal infections have also been described. All these factors can generate a long-term inflammatory state characterized by the persistent activation of the immune system, the frequent release of pro-inflammatory cytokines, and the constant production of reactive oxygen species that result in a chronic damage/repair cycle, subsequently inducing the loss of the normal architecture of the gallbladder mucosa that leads to the development of GBC.

• #37 Environmental and Lifestyle Risk Factors in the Carcinogenesis of Gallbladder Cancer

  https://www.mdpi.com/2075-4426/12/2/234

  The cumulative evidence described in this review shows that GBC is a chronic inflammatory disease promoted by different risk factors including gallstone disease (GSD), sedentary lifestyle, smoking, alcohol consumption, metabolic disorders, high-fat diet, hypercholesterolemia, and some types of infections. In addition, gallbladder carcinogenesis has been strongly associated with specific populations (e.g., Mapuche ancestry), possibly because these populations present some genetic background that predispose them to being more susceptible to gallstone formation and hence a greater predisposition to the development GBC, which could explain the high incidence of GBC in this population.

• #38 Gallbladder cancer stem cell markers: An updated brief review

  https://www.oatext.com/Gallbladder-cancer-stem-cell-markers-An-updated-brief-review.php

  Gallbladder cancer is the most aggressive gastrointestinal tract cancer. […] Cancer stem cell hypothesis provides an important cellular mechanism to understand the abnormal behavior exhibited by the tumors. […] Therefore, cancer stem cell markers may serve as novel therapeutic targets as well as diagnostic or prognostic markers in gallbladder cancer. […] Poor prognosis shows low survival. […] Chronic inflammation and dysplasia have been proposed to explain the association of gallstones and cancer. […] Cancer stem cell research hypothesized that the mutation in stem cell niche population during development results in the reproduction of mutated daughter cells, these cells are very much closer to become tumor and their number increase the chance of cancerous mutation. […] Today, increasing evidence has confirmed that the cancers consist of small population of cancer stem cells or tumor initiating cells (TIC) which are considered being responsible for the recurrence of cancer and metastasis.

• #39 Gallbladder cancer stem cell markers: An updated brief review

  https://www.oatext.com/Gallbladder-cancer-stem-cell-markers-An-updated-brief-review.php

  The concept of CSCs is derived from the similarities that exist between normal stem cells and CSCs. […] Advancement of knowledge in the concept of Cancer Stem Cells and their encouraging results suggest new directions in the treatment of cancer as they are thought to be responsible for tumor initiation, progression, therapy resistance, relapse and metastasis. […] The well accepted CSC markers of are CD44, CD24, CD133, CD166 and EpCAM and a few more and most of them are also reported in Gall Bladder Cancer. […] The signaling pathways utilized by both normal stem cells and CSCs overlap and are based on embryonic signaling pathways which allow self-renewal. […] The positive expression rates of Annexin A3 in gallbladder cancer was reported as significantly higher than that in cholecystitis, with important factor for the initiation and progression of human gallbladder cancer.

• #40 Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors | eLife

  https://elifesciences.org/articles/78636

  We aimed to elucidate the evolutionary trajectories of gallbladder adenocarcinoma (GBAC) using multi-regional and longitudinal tumor samples. […] Subclonal diversity arose early in precancerous lesions and clonal selection was a common event during malignant transformation in GBAC. However, selected cancer clones continued to evolve and thus maintained subclonal diversity in metastatic tumors. […] This is the first dedicated study of clonal evolution in gallbladder cancer that involves precancerous, transformed primary and metastatic lesions. The main insights include the finding of subclonal diversity in precancerous lesions, a degree of bottlenecking during transformation but maintenance of some clonal complexity through metastases. […] Cancer cells undergo clonal evolution by acquiring additional mutations and thus exhibit more aggressive phenotypes, including invasion and metastasis.

• #41 Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors | eLife

  https://elifesciences.org/articles/78636

  In our analysis of carcinogenesis, we discovered three common themes. First, most mutations in frequently altered genes in primary GBAC are detected in concurrent BilIN (10 of 13, 76.9%), but a substantial proportion was subclonal. Second, branching evolution and subclonal diversity are commonly observed at the BilIN stage. Third, one subclone in BilIN commonly shrinks in the primary tumors, while the other subclones undergo linear and branching evolution, maintaining subclonal diversity after the BilIN stage. […] In the analysis of metastasis, the following three phenomena are observed. First, subclonal expansion is frequent (8 of 11 patients, 72.7%) and some subclones expand substantially in metastatic tumors, leading to increased subclonal diversity. […] Our study found the possibility of metastasis-to-metastasis spread in GB-A2.

• #42 Comprehensive single-cell analysis deciphered microenvironmental dynamics and immune regulator olfactomedin 4 in pathogenesis of gallbladder cancer | Gut

  https://gut.bmj.com/content/73/9/1529

  These findings offer a valuable resource for understanding the pathogenesis of gallbladder diseases and indicate OLFM4 as a potential biomarker and therapeutic target for GBC. […] The comprehensive transcriptome atlas offers insights into GBC heterogeneity and precancerous transitions, laying a groundwork for devising targeted therapies through understanding the complex microenvironment and genetic variations. […] Our study sheds light on key molecular elements of GBC pathogenesis but needs further exploration due to limitations like small sample sizes in certain GBC types, affecting the generalisability of our findings.

• #43 Oncology Letters

  https://www.spandidos-publications.com/ol/18/2/1365?text=fulltext

  Expression of Bmi-1 in gallbladder carcinoma and its clinicopathology and mechanisms of regulation of human gallbladder carcinoma cell proliferation were investigated. […] The positive expression rate of Bmi-1 protein in gallbladder carcinoma tissues was significantly higher than that in normal gallbladder tissues. […] Gallbladder carcinoma is the most common malignant tumor of the biliary system. […] Therefore, in-depth study of key molecules in the development of gallbladder cancer, exploring the molecular mechanism of gallbladder cancer proliferation, and screening for effective diagnostic and therapeutic targets is critical for the future treatment of gallbladder cancer. […] The role of Bmi-1 in tumor formation has become a research hotspot in different types of cancer. […] However, whether Bmi-1 is involved in the development of gallbladder cancer and its role in gallbladder cancer is unclear.

• #44 Oncology Letters

  https://www.spandidos-publications.com/10.3892/ol.2019.10408

  Expression of Bmi-1 in gallbladder carcinoma and its clinicopathology and mechanisms of regulation of human gallbladder carcinoma cell proliferation were investigated. […] The positive expression rate of Bmi-1 protein in gallbladder carcinoma tissues was significantly higher than that in normal gallbladder tissues. […] Gallbladder carcinoma is the most common malignant tumor of the biliary system. […] Therefore, in-depth study of key molecules in the development of gallbladder cancer, exploring the molecular mechanism of gallbladder cancer proliferation, and screening for effective diagnostic and therapeutic targets is critical for the future treatment of gallbladder cancer. […] The role of Bmi-1 in tumor formation has become a research hotspot in different types of cancer. […] However, whether Bmi-1 is involved in the development of gallbladder cancer and its role in gallbladder cancer is unclear.

• #45 Oncology Letters

  https://www.spandidos-publications.com/10.3892/ol.2019.10408

  The aim of the study was to explore the mechanism of the action of Bmi-1 in the occurrence and development of gallbladder carcinoma, and provide a theoretical basis for understanding the molecular mechanism and clinical treatment of gallbladder cancer. […] The expression of Bmi-1 protein in gallbladder carcinoma tissues was associated with tumor differentiation degree and stage. […] After transfecting Bmi1-si RNA and Bmi1-NC vector into gallbladder cancer cell line GBC-SD, RT-qPCR showed that Bmi-1 expression level in GBC-SD-Bmi1-si RNA was significantly lower than that in GBC-SD-Bmi1-NC and GBC-SD cells, which proved that Bmi1-si RNA played an inhibitory role. […] This study demonstrates that targeted inhibition of Bmi-1 expression can affect the proliferation and apoptosis of gallbladder cancer cells.

• #46 Oncology Letters

  https://www.spandidos-publications.com/10.3892/ol.2019.10408

  The molecular mechanism is related to the decreased expression of cyclin D1 and CDK2, decreased expression of anti-apoptotic protein Bcl-2, and increased expression of proapoptotic protein Bax and caspase 3, which confirms that Bmi-1 is a potential target for clinical treatment of gallbladder cancer.

• #47

  https://journals.lww.com/otm/fulltext/2023/08000/controversies_and_future_directions_in_the.2.aspx

  Gallbladder cancer (GBC) is a rare malignancy worldwide, with 140,000 new patients each year and more than 100,000 deaths annually. […] Comparative mutational profiles will provide more information on the pathogenesis of GBC. […] Regional differences in the pathogenesis of GBCs have also been demonstrated in GBC pathogenesis. A report published in Cancer in 2019 described a study conducted with patients with GBC from 3 countries (the United States, Chile, and Japan). The difference identified in clinicopathological variables suggests the possibility of a distinct GBC pathogenesis in Japanese patients, which may be supported by the differences discovered in the mutational pattern in this study. […] Another recent study of Chinese and US patients with GBC demonstrated differences in genetic aberrations between both countries, which will potentially guide and influence personalized treatment options in the future. […] A comparative mutational study of the Andes-related countries (Chile, Argentina, Peru, Ecuador, Bolivia) will be able to provide new insights in this field.

• #48

  https://link.springer.com/article/10.1007/s00210-024-03279-1

  Overall, dysfunctional lncRNA regulatory circuits offer multiple avenues for precision medicine approaches to improve early GBC detection and overcome this deadly cancer. They have the potential to serve as novel biomarkers as they are detectable in bodily fluids and tissues. These findings enhance gallbladder treatments, mitigating resistance to chemo- and radiotherapy.

• #49 Gallbladder cancer stem cell markers: An updated brief review

  https://www.oatext.com/Gallbladder-cancer-stem-cell-markers-An-updated-brief-review.php

  Loss of E-cadherin expression was high in gallbladder cancer, when compared with cholecystitis and xanthogranulomatous cholecystis cases and its expression might be useful prognostic marker. […] Enormous novel approaches to target CSCs have received much attention over the past several years. […] The rise of the cancer stem cell hypothesis provides a new approach to eradicate malignancies.

• #50 Gallbladder cancer: lessons from a rare tumour – SEARCH

  https://primo.qatar-weill.cornell.edu/discovery/fulldisplay/cdi_proquest_miscellaneous_66836340/974WCMCIQ_INST:VU1

  Gallbladder cancer is a relatively rare form of malignancy about which our knowledge is scant. However, a unique combination of predisposing factors — including genetic predisposition, geographic distribution, female gender bias, chronic inflammation and congenital developmental abnormalities — makes this type of cancer unique and offers potential for understanding cancer pathogenesis in general. An understanding of how these risk factors contribute to the molecular basis of the disease is essential for understanding the origins of this unusual cancer.

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