Chemoresistance in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While the incidence of pancreatic cancer is displaying a rising tendency every year, the mortality rate has not decreased significantly because of late diagnosis, early metastasis, and limited reaction to chemotherapy or radiotherapy. Adjuvant chemotherapy after surgical resection is typically the preferred option to treat early pancreatic cancer. Although 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel can profoundly improve the prognosis of advanced pancreatic cancer, the development of chemoresistance still leads to poor clinical outcomes. Chemoresistance is multifactorial as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. Therefore, we outline new perspectives for enhancing the efficacy of gemcitabine after reviewing the related factors of gemcitabine metabolism, mechanism of action, and chemoresistance

Extramedullary plasmacytoma: Tumor occurrence and therapeutic concepts—A follow-up

Background Extramedullary plasmacytoma (EMP) is a solitary tumor consisting of neoplastic plasma cells, with very little to no bone marrow involvement. EMPs are usually located in the head and neck region, but can also occur along the digestive tract, in lungs, or extremities. Methods Following our publication on EMP, which appeared in 1999 (Cancer 85:2305–14), we conducted a literature search for EMP-related reports published between 1999 and 2021. The documented cases, as well as 14 of our own patients from the ENT Clinic Erlangen, were extensively analyzed. Results Between 1998 and 2021, 1134 patients with EMP were reported, for whom information about the tumor localization was available. Among those, 62.4% had EMP in the head and neck area and 37.6% in other body regions. Data on therapy were reported in 897 patients, including 34.3% who received radiation, 28.1% surgery, 22.6% a combination of surgery and radiation, and 15.9% another therapy. In 76.9% patients no recurrence or transformation to multiple myeloma (MM) was reported, 12.8% showed local recurrence and 10.2% developed MM. Radiotherapy alone was associated with a tendency for increased occurrence of MM. In patients with EMP of head and neck area, combination therapy (surgery and radiation) resulted in a 5-year overall survival rate of 98.3%, surgery alone of 92.4%, and radiotherapy of 92.7%. Conclusions Collectively, our analyses indicate that surgical resection alone can achieve long-term tumor control in patients with EMP, if the tumor can be removed within safe limits without causing serious functional impairment. However, if this is not certain, either radiation or a combination of surgery and radiation therapy is suggested as an effective means of local tumor control

The role of CD98hc in renal cancer cell behavior

CD98hc (SLC3A2), ein Typ II transmembranes Protein, besitzt eine heterodimere Struktur und besteht aus einer schweren und leichten Untereinheit. Erstmals als 4F2 antigen identifiziert, ist CD98hc ein Zelloberflächenmolekül, welches eine erhöhte Expression in T - Zellen sowie in stark proliferierenden Zellen aufweist. Einerseits interagiert CD98hc - über Disulfidbrücken verbunden- mit einer von sieben verschiedenen leichten Ketten, diese sind Aminosäurentransporter, andererseits interagiert CD98hc mit der cytoplasmatischen Domäne von Integrinen und mediiert dadurch Adhäsions - induzierte Signaltransduktion [1]. Eine Deletion von CD98hc in Mäusen führt zwischen dem embryonalen Tag E 3,5 und E 9,5 zur Letalität [2, 3]. In in vivo Xenotransplantversuchen konnte gezeigt werden, dass eine Deletion von CD98hc in embryonalen Stammzellen die Fähigkeit Teratokarzinome zu bilden blockiert, desweiteren führ dies zu verringertem Zellwachstum und Apoptose [4]. Eine Überexpression von CD98hc hingegen führte in murinen Fiboblasten zu einem erhöhten Wachstum unabhängig von Adhäsion [5]. In dieser PhD - Arbeit wurde CD98hc als neuer und einzigartiger diagnostischer Marker für das maligne Nierenzellkarzinom (RCC) identifiziert, dazu gehören das klarzellige RCC sowie das papilläre RCC und das Chromophobe RCC. Hierbei korrelierte das Level der CD98hc Expression mit dem Grad der Differenzierung, wobei das maligne und aggressivere Grad 3/ Grad 4 ccRCC und Typ II pRCC eine signifikant höhere CD98hc Expression in semiquantitativen Analysen aufweisen. Mittels einer Kombination aus Über- und Unterexpression von CD98hc in in vitro Versuchen, konnte bisher erstmalig die Bedeutung von CD98hc auf das Tumorzellverhalten, wie Tumorzell-Proliferation, Anoikis, Zellmigration und Zell-Spreading, gezeigt werden. ^Zusammenfassend zeigen diese Daten, dass CD98hc nicht nur ein neuartiger Biomarker für das maligne Nierenzellkarzinom ist, sonder auch ein potentielles diagnostisches Target für maligne Erkrankungen darstellen kann.CD98(SLC3A2) has a heteromeric structure, consisting of a heavy subunit linked to a light subunit via disulfide bridges, CD98, originally identified as the 4F2 antigen, is a cell surface molecule, which is highly expressed in activated T cells, proliferating endothelial cells, and proliferating fibroblasts. The heavy subunit is a type II transmembrane glycoprotein associated with one of seven different light chains. The latter ones provide amino acid transport activity of CD98, while the heavy chain (CD98hc) is thought to mediate adhesion induced signal transduction via integrins [1]. Disruption of the CD98hc gene led to embryonic lethality between day E 3.5 and E 9.5 [2, 3]. Deletion of CD98hc in embryonic stem cells blocked their ability to form teratocarcinomas in vivo transplants in mice [2], while inhibition of CD98hc in vitro led to reduced cell growth and apoptosis in embryonic stem cells [4]. Over-expression of CD98hc in murine fibroblasts resulted in anchorage-independent growth [5]. In this PhD - thesis CD98hc was identified as a novel diagnostic marker for malignant renal cell cancer, among them clear cell renal cell cancer, papillary as well as chromphobe renal cell cancer. Thereby, level of CD98hc expression correlated with grade of differentiation, whereby the more malignant grade3/ grade4 ccRCC or type II pRCC revealed significant higher CD98hc expression in semi-quantitative analyses. Furthermore, by a combination of loss and gain of function approaches a hitherto undescribed functional role of CD98hc in tumor cell behavior such as tumor cell proliferation, cell survival upon detachment, cell migration or spreading was revealed. In conclusion these data indicated that CD98hc is not only a novel biomarker in RCC, but might also represent a pathological diagnostic target in cancer.submitted by Marina PöttlerAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in dt. SpracheWien, Med. Univ., Diss., 2012OeBB(VLID)171549