Advances in Cancer Research最新文献

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality rate. Within the next decade, PDAC is projected to become the second leading cause of cancer-associated death in the United States. Understanding the pathophysiology of PDAC tumorigenesis and metastases is crucial toward developing new therapeutics. One of the challenges in cancer research is generating in vivo models that closely recapitulate the genomic, histological, and clinical characteristics of human tumors. An ideal model for PDAC not only captures the tumor and stromal environment of human disease, but also allows for mutational control and is easy to reproduce in terms of time and cost. In this review, we highlight evolution of in vivo models for PDAC including spontaneous tumors models (i.e., chemical induction, genetic modification, viral delivery), implantation models including patient derived xenografts (PDX), and humanized PDX. We discuss the implementation of each system and evaluate the benefits and shortcomings of these models. Overall, this review provides a broad overview of prior and current techniques of in vivo PDAC modeling and their associated challenges.

Since the discovery of tyrosine phosphorylation being a critical modulator of cancer signaling, proteins regulating phosphotyrosine levels in cells have fast become targets of therapeutic intervention. The nonreceptor protein tyrosine phosphatase (PTP) coded by the PTPN11 gene "SHP2" integrates phosphotyrosine signaling from growth factor receptors into the RAS/RAF/ERK pathway and is centrally positioned in processes regulating cell development and oncogenic transformation. Dysregulation of SHP2 expression or activity is linked to tumorigenesis and developmental defects. Even as a compelling anti-cancer target, SHP2 was considered "undruggable" for a long time owing to its conserved catalytic PTP domain that evaded drug development. Recently, SHP2 has risen from the "undruggable curse" with the discovery of small molecules that manipulate its intrinsic allostery for effective inhibition. SHP2's unique domain arrangement and conformation(s) allow for a truly novel paradigm of inhibitor development relying on skillful targeting of noncatalytic sites on proteins. In this review we summarize the biological functions, signaling properties, structural attributes, allostery and inhibitors of SHP2.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer in the United States. Additionally, the low survival rate makes PDAC the third-leading cause of cancer-related mortality in the United States, and it is projected that by 2030, it will become the second-leading cause of cancer mortality. Several biological factors contribute to PDAC aggressiveness, and their understanding will narrow the gap from biology to clinical care of PDAC, leading to earlier diagnoses and the development of better treatment options. In this review, we describe the origins of PDAC highlighting the role of cancer stem cells (CSC). CSC, also known as tumor initiating cells, which exhibit a unique metabolism that allows them to maintain a highly plastic, quiescent, immune- and therapy-evasive state. However, CSCs can exit quiescence during proliferation and differentiation, with the capacity to form tumors while constituting a small population in tumor tissues. Tumorigenesis depends on the interactions between CSCs and other cellular and non-cellular components in the microenvironment. These interactions are fundamental to support CSC stemness and are maintained throughout tumor development and metastasis. PDAC is characterized by a massive desmoplastic reaction, which result from the deposition of high amounts of extracellular matrix components by stromal cells. Here we review how this generates a favorable environment for tumor growth by protecting tumor cells from immune responses and chemotherapy and inducing tumor cell proliferation and migration, leading to metastasis formation ultimately leading to death. We emphasize the interactions between CSCs and the tumor microenvironment leading to metastasis formation and posit that better understanding and targeting of these interactions will improve patient outcomes.

Tumor growth and metastasis can be promoted by a small sub-population of cancer cells, termed cancer stem-like cells (CSCs). While CSCs possess capability in self-renewing and differentiating, the hierarchy of CSCs during tumor growth is highly plastic. This plasticity in CSCs fate and function can be regulated by signals from the tumor microenvironment. One emerging pathway in CSCs that connects the alteration in microenvironment and signaling network in cancer cells is the hexosamine biosynthetic pathway (HBP). The final product of HBP, UDP-N-acetylglucosamine (UDP-GlcNAc), is utilized for glycosylating of membrane and secreted proteins, but also nuclear and cytoplasmic proteins by the post-translational modification O-GlcNAcylation. O-GlcNAcylation and its enzyme, O-GlcNAc transferase (OGT), are upregulated in nearly all cancers and been linked to regulate many cancer cell phenotypes. Recent studies have begun to connect OGT and O-GlcNAcylation to regulation of CSCs. In this review, we will discuss the emerging role of OGT and O-GlcNAcylation in regulating fate and plasticity of CSCs, as well as the potential in targeting OGT/O-GlcNAcylation in CSCs.

Pancreatic Ductal Adenocarcinoma (PDAC), commonly called pancreatic cancer, is aggressive cancer usually detected at a late stage, limiting treatment options with modest clinical responses. It is projected that by 2030, PDAC will be the second most common cause of cancer-related mortality in the United States. Drug resistance in PDAC is common and significantly affects patients' overall survival (OS). Oncogenic KRAS mutations are nearly uniform in PDAC, affecting over 90% of patients. However, effective drugs directed to target prevalent KRAS mutants in pancreatic cancer are not in clinical practice. Accordingly, efforts are continued on identifying alternative druggable target(s) or approaches to improve patient outcomes with PDAC. In most PDAC cases, the KRAS mutations turn-on the RAF-MEK-MAPK pathways, leading to pancreatic tumorigenesis. The MAPK signaling cascade (MAP4K→MAP3K→MAP2K→MAPK) plays a central role in the pancreatic cancer tumor microenvironment (TME) and chemotherapy resistance. The immunosuppressive pancreatic cancer TME is another unfavorable factor affecting the therapeutic efficacy of chemotherapy and immunotherapy. The immune checkpoint proteins (ICPs), including CTLA-4, PD-1, PD-L1, and PD-L2, are critical players in T cell dysfunction and pancreatic tumor cell growth. Here, we review the activation of MAPKs, a molecular trait of KRAS mutations and their impact on pancreatic cancer TME, chemoresistance, and expression of ICPs that could influence the clinical outcomes in PDAC patients. Therefore, understanding the interplay between MAPK pathways and TME could help to design rational therapy combining immunotherapy and MAPK inhibitors for pancreatic cancer treatment.

A fundamental step of tumor metastasis is tumor cell migration away from the primary tumor site. One mode of migration that is essential but still understudied is collective invasion, the process by which clusters of cells move in a coordinated fashion. In recent years, there has been growing interest to understand factors regulating collective invasion, with increasing number of studies investigating the biomechanical regulation of collective invasion. In this review we discuss the dynamic relationship between tumor microenvironment cues and cell response by first covering mechanical factors in the microenvironment and second, discussing the mechanosensing pathways utilized by cells in collective clusters to dynamically respond to mechanical matrix cues. Finally, we discuss model systems that have been developed which have increased our understanding of the mechanical factors contributing to tumor progression.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related mortality worldwide and 80%-90% of HCC develops in patients that have underlying cirrhosis. Better methods of surveillance are needed to increase early detection of HCC and the proportion of patients that can be offered curative therapies. Recent work in novel mass spec-based methods for glycomic and glycopeptide analysis for discovery and confirmation of markers for early detection of HCC versus cirrhosis is reviewed in this chapter. Results from recent work in these fields by several groups and the progress made in developing markers of early HCC which can outperform the current serum-based markers are described and discussed. Also, recent developments in isoform analysis of glycans and glycopeptides and in various mass spec fragmentation methods will be described and discussed.

The back-breaking resistance mechanisms generated by lung cancer cells against epidermal growth factor receptor (EGFR), KRAS and Janus kinase 2 (JAK2) directed therapies strongly prioritizes the requirement of novel therapies which are perfectly tolerated, potentially cytotoxic and can reinstate the drug-sensitivity in lung cancer cells. Enzymatic proteins modifying the post-translational modifications of nucleosome-integrated histone substrates are appearing as current targets for defeating various malignancies. Histone deacetylases (HDACs) are hyperexpressed in diverse lung cancer types. Blocking the active pocket of these acetylation erasers through HDAC inhibitors (HDACi) has come out as an optimistic therapeutic recourse for annihilating lung cancer. This article in the beginning gives an overview about lung cancer statistics and predominant lung cancer types. Succeeding this, compendium about conventional therapies and their serious drawbacks has been provided. Then, connection of uncommon expression of classical HDACs in lung cancer onset and expansion has been detailed. Moreover, keeping the main theme in view this article deeply discusses HDACi in the context of aggressive lung cancer as single agents and spotlights various molecular targets suppressed or induced by these inhibitors for engendering cytotoxic effect. Most particularly, the raised pharmacological effects achieved on using these inhibitors in concerted form with other therapeutic molecules and the cancer-linked pathways altered by this procedure are described. The positive direction towards further heightening of efficacy and the pressing requirement of exhaustive clinical assessment has been proposed as a new focus point.

The brine shrimp (Artemia), releases embryos that can remain dormant for up to a decade. Molecular and cellular level controlling factors of dormancy in Artemia are now being recognized or applied as active controllers of dormancy (quiescence) in cancers. Most notably, the epigenetic regulation by SET domain-containing protein 4 (SETD4), is revealed as highly conserved and the primary control factor governing the maintenance of cellular dormancy from Artemia embryonic cells to cancer stem cells (CSCs). Conversely, DEK, has recently emerged as the primary factor in the control of dormancy exit/reactivation, in both cases. The latter has been now successfully applied to the reactivation of quiescent CSCs, negating their resistance to therapy and leading to their subsequent destruction in mouse models of breast cancer, without recurrence or metastasis potential. In this review, we introduce the many mechanisms of dormancy from Artemia ecology that have been translated into cancer biology, and herald Artemia's arrival on the model organism stage. We show how Artemia studies have unlocked the mechanisms of the maintenance and termination of cellular dormancy. We then discuss how the antagonistic balance of SETD4 and DEK fundamentally controls chromatin structure and consequently governs CSCs function, chemo/radiotherapy resistance, and dormancy in cancers. Many key stages from transcription factors to small RNAs, tRNA trafficking, molecular chaperones, ion channels, and links with various pathways and aspects of signaling are also noted, all of which link studies in Artemia to those of cancer on a molecular and/or cellular level. We particularly emphasize that the application of such emerging factors as SETD4 and DEK may open new and clear avenues for the treatment for various human cancers.