Advances in Cancer Research最新文献

Melanoma is a highly aggressive skin cancer with poor outcomes associated with distant metastasis. Intrinsic properties of melanoma cells alongside the crosstalk between melanoma cells and surrounding microenvironment determine the tumor behavior. Galectin-3 (Gal-3), a ß-galactoside-binding lectin, has emerged as a major effector in cancer progression, including melanoma behavior. Data from melanoma models and patient studies reveal that Gal-3 expression is dysregulated, both intracellularly and extracellularly, throughout the stages of melanoma progression. This review summarizes the most recent data and hypotheses on Gal-3 and its tumor-modulating functions, highlighting its role in driving melanoma growth, invasion, and metastatic colonization. It also provides insight into potential Gal-3-targeted strategies for melanoma diagnosis and treatment.

Mucin-domain glycoproteins are highly O-glycosylated cell surface and secreted proteins that serve as both biochemical and biophysical modulators. Aberrant expression and glycosylation of mucins are known hallmarks in numerous malignancies, yet mucin-domain glycoproteins remain enigmatic in the broad landscape of cancer glycobiology. Here we review the multifaceted roles of mucins in cancer through the lens of the analytical and biochemical methods used to study them. We also describe a collection of emerging tools that are specifically equipped to characterize mucin-domain glycoproteins in complex biological backgrounds. These approaches are poised to further elucidate how mucin biology can be understood and subsequently targeted for the next generation of cancer therapeutics.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging disease usually diagnosed at advanced or metastasized stage. By this year end, there are an expected increase in 62,210 new cases and 49,830 deaths in the United States, with 90% corresponding to PDAC subtype alone. Despite advances in cancer therapy, one of the major challenges combating PDAC remains tumor heterogeneity between PDAC patients and within the primary and metastatic lesions of the same patient. This review describes the PDAC subtypes based on the genomic, transcriptional, epigenetic, and metabolic signatures observed among patients and within individual tumors. Recent studies in tumor biology suggest PDAC heterogeneity as a major driver of disease progression under conditions of stress including hypoxia and nutrient deprivation, leading to metabolic reprogramming. We therefore advance our understanding in identifying the underlying mechanisms that interfere with the crosstalk between the extracellular matrix components and tumor cells that define the mechanics of tumor growth and metastasis. The bilateral interaction between the heterogeneous tumor microenvironment and PDAC cells serves as another important contributor that characterizes the tumor-promoting or tumor-suppressing phenotypes providing an opportunity for an effective treatment regime. Furthermore, we highlight the dynamic reciprocating interplay between the stromal and immune cells that impact immune surveillance or immune evasion response and contribute towards a complex process of tumorigenesis. In summary, the review encapsulates the existing knowledge of the currently applied treatments for PDAC with emphasis on tumor heterogeneity, manifesting at multiple levels, impacting disease progression and therapy resistance under stress.

Epithelial to mesenchymal transition (EMT) is a complex cellular program that alters epithelial cells and induces their transformation into mesenchymal cells. While essential to normal developmental processes such as embryogenesis and wound healing, EMT has also been linked to the development and progression of various diseases, including fibrogenesis and tumorigenesis. Under homeostatic conditions, initiation of EMT is mediated by key signaling pathways and pro-EMT-transcription factors (EMT-TFs); however, in certain contexts, these pro-EMT regulators and programs also drive cell plasticity and cell stemness to promote oncogenesis as well as metastasis. In this review, we will explain how EMT and EMT-TFs mediate the initiation of pro-cancer states and how they influence late-stage progression and metastasis in pancreatic ductal adenocarcinoma (PDAC), the most severe form of pancreatic cancer.

The use of chemotherapeutic agents and the development of new cancer therapies over the past few decades has consequently led to the emergence of myriad therapeutic resistance mechanisms. Once thought to be explicitly driven by genetics, the coupling of reversible sensitivity and absence of pre-existing mutations in some tumors opened the way for discovery of drug-tolerant persisters (DTPs): slow-cycling subpopulations of tumor cells that exhibit reversible sensitivity to therapy. These cells confer multi-drug tolerance, to targeted and chemotherapies alike, until the residual disease can establish a stable, drug-resistant state. The DTP state can exploit a multitude of distinct, yet interlaced, mechanisms to survive otherwise lethal drug exposures. Here, we categorize these multi-faceted defense mechanisms into unique Hallmarks of Cancer Drug Tolerance. At the highest level, these are comprised of heterogeneity, signaling plasticity, differentiation, proliferation/metabolism, stress management, genomic integrity, crosstalk with the tumor microenvironment, immune escape, and epigenetic regulatory mechanisms. Of these, epigenetics was both one of the first proposed means of non-genetic resistance and one of the first discovered. As we describe in this review, epigenetic regulatory factors are involved in most facets of DTP biology, positioning this hallmark as an overarching mediator of drug tolerance and a potential avenue to novel therapies.

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.

The ultimate goal of cancer therapy is the elimination of disease from patients. Most directly, this occurs through therapy-induced cell death. Therapy-induced growth arrest can also be a desirable outcome, if prolonged. Unfortunately, therapy-induced growth arrest is rarely durable and the recovering cell population can contribute to cancer recurrence. Consequently, therapeutic strategies that eliminate residual cancer cells reduce opportunities for recurrence. Recovery can occur through diverse mechanisms including quiescence or diapause, exit from senescence, suppression of apoptosis, cytoprotective autophagy, and reductive divisions resulting from polyploidy. Epigenetic regulation of the genome represents a fundamental regulatory mechanism integral to cancer-specific biology, including the recovery from therapy. Epigenetic pathways are particularly attractive therapeutic targets because they are reversible, without changes in DNA, and are catalyzed by druggable enzymes. Previous use of epigenetic-targeting therapies in combination with cancer therapeutics has not been widely successful because of either unacceptable toxicity or limited efficacy. The use of epigenetic-targeting therapies after a significant interval following initial cancer therapy could potentially reduce the toxicity of combination strategies, and possibly exploit essential epigenetic states following therapy exposure. This review examines the feasibility of targeting epigenetic mechanisms using a sequential approach to eliminate residual therapy-arrested populations, that might possibly prevent recovery and disease recurrence.