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Adv Cancer Res 2022 ;154:xiii-xiv

Adv Cancer Res 2022 24;154:93-140. Epub 2022 Feb 24.

The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States; Department of Radiation Oncology, The Ohio State University, Columbus, OH, United States. Electronic address:

Over the last couple of decades, it has become increasingly apparent that the tumor microenvironment (TME) mediates every step of cancer progression and solid tumors are only able to metastasize with a permissive TME. This intricate interaction of cancer cells with their surrounding TME, or stroma, is becoming more understood with an ever greater knowledge of tumor-stromal signaling pairs such as platelet-derived growth factors (PDGF) and their cognate receptors. We and others have focused our research efforts on understanding how tumor-derived PDGFB activates platelet-derived growth factor receptor beta (PDGFRβ) signaling specifically in the breast cancer TME. Read More

Adv Cancer Res 2022 26;154:47-91. Epub 2022 Feb 26.

Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH, United States; The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States. Electronic address:

In most solid tumors, malignant cells coexist with non-cancerous host tissue comprised of a variety of extracellular matrix components and cell types, notably fibroblasts, immune cells, and endothelial cells. It is becoming increasingly evident that the non-cancerous host tissue, often referred to as the tumor stroma or the tumor microenvironment, wields tremendous influence in the proliferation, survival, and metastatic ability of cancer cells. The tumor stroma has an active biological role in the transmission of signals, such as growth factors and chemokines that activate oncogenic signaling pathways by autocrine and paracrine mechanisms. Read More

Adv Cancer Res 2022 18;154:227-251. Epub 2022 Mar 18.

Department of Neuroscience, University of Kentucky College of Medicine, Lexington, KY, United States; Markey Cancer Center, Lexington, KY, United States. Electronic address:

The tumor microenvironment contains a heterogeneous population of stromal and cancer cells that engage in metabolic crosstalk to ultimately promote tumor growth and contribute to progression. Due to heterogeneity within solid tumors, pooled mass spectrometry workflows are less sensitive at delineating unique metabolic perturbations between stromal and immune cell populations. Two critical, but understudied, facets of glucose metabolism are anabolic pathways for glycogen and N-linked glycan biosynthesis. Read More

Adv Cancer Res 2022 18;154:203-226. Epub 2022 Mar 18.

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

Decades of research have concluded that disruptions to Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) have profound effects on cancer progression. However, as our understanding of the tumor stroma has evolved, we can appreciate that disruptions to tumor suppressors such as PTEN should not be studied solely in an epithelial context. Inactivation of PTEN in the stroma is associated with worse outcomes in human cancers, therefore, it is important to understand activities regulated downstream of PTEN in stromal compartments. Read More

Adv Cancer Res 2022 30;154:169-201. Epub 2022 Mar 30.

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

Pancreas and breast cancers both contain abundant stromal components within the tumor tissues. A prominent cell type within the stroma is cancer-associated fibroblasts (CAFs). CAFs play critical and complex roles establishing the tumor microenvironment to either promote or prevent tumor progression. Read More

Adv Cancer Res 2022 18;154:15-45. Epub 2022 Mar 18.

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States.

Cancer is a complex disease and a significant cause of mortality worldwide. Over the course of nearly all cancer types, collagen within the tumor microenvironment influences emergence, progression, and metastasis. This review discusses collagen regulation within the tumor microenvironment, pathological involvement of collagen, and predictive values of collagen and related extracellular matrix components in main cancer types. Read More

Adv Cancer Res 2022 24;154:141-168. Epub 2022 Feb 24.

Cancer Signaling and Epigenetics Program, Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, United States. Electronic address:

As part of the connective tissue, activated fibroblasts play an important role in development and disease pathogenesis, while quiescent resident fibroblasts are responsible for sustaining tissue homeostasis. Fibroblastic activation is particularly evident in the tumor microenvironment where fibroblasts transition into tumor-supporting cancer-associated fibroblasts (CAFs), with some CAFs maintaining tumor-suppressive functions. While the tumor-supporting features of CAFs and their fibroblast-like precursors predominantly function through paracrine chemical communication (e. Read More

Adv Cancer Res 2022 5;154:1-14. Epub 2022 Apr 5.

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

Carcinoma is defined as cancer arising from the epithelial cells that line an organ or tissue. The most common carcinoma in males arises in the prostate and breast in females; while the most significant cause of cancer related mortality in the United States is carcinoma of the lung. Cancers typically begin as a clonal proliferation of cells that have acquired distinct mutations, which then progress to invasive carcinoma as the cells breach the underlying basement membrane associated with the tissue of origin. Read More

Adv Cancer Res 2022 ;153:xiii-xiv

Adv Cancer Res 2022 20;153:63-99. Epub 2021 Aug 20.

Cancer Cell Biology and Drug Discovery Group, Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg. Electronic address:

Disruption of the native membrane organization of Ras by the farnesyltransferase inhibitor tipifarnib in the late 1990s constituted the first indirect approach to drug target Ras. Since then, our understanding of how dynamically Ras shuttles between subcellular locations has changed significantly. Ras proteins have to arrive at the plasma membrane for efficient MAPK-signal propagation. Read More

Adv Cancer Res 2022 7;153:305-341. Epub 2021 Aug 7.

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

The RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and capillary malformation-arteriovenous malformation syndrome. Many of these genetic disorders share clinical features in common such as abnormal facies, short stature, varying degrees of cognitive impairment, cardiovascular abnormalities, skeletal abnormalities and a predisposition to develop benign and malignant neoplasms. Read More

Adv Cancer Res 2022 23;153:29-61. Epub 2021 Aug 23.

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

The RAS family of small GTPases are among the most frequently mutated oncogenes in human cancer. Approximately 20% of cancers harbor a RAS mutation, and >150 different missense mutations have been detected. Many of these mutations have mutant-specific biochemical defects that alter nucleotide binding and hydrolysis, effector interactions and cell signaling, prompting renewed efforts in the development of anti-RAS therapies, including the mutation-specific strategies. Read More

Adv Cancer Res 2022 26;153:267-304. Epub 2021 Aug 26.

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address:

RAS mutations are among the most frequent oncogenic drivers observed in human cancers. With a lack of available treatment options, RAS-mutant cancers account for many of the deadliest cancers in the United States. Recent studies established that altered metabolic requirements are a hallmark of cancer, and many of these alterations are driven by aberrant RAS signaling. Read More

Adv Cancer Res 2022 13;153:237-266. Epub 2021 Aug 13.

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States; Ralph H. Johnson VA Medical Center, Charleston, SC, United States. Electronic address:

RAS proteins represent critical drivers of tumor development and thus are the focus of intense efforts to pharmacologically inhibit these proteins in human cancer. Although recent success has been attained in developing clinically efficacious inhibitors to KRAS, there remains a critical need for developing approaches to inhibit additional mutant RAS proteins. A number of anti-RAS biologics have been developed which reveal novel and potentially therapeutically targetable vulnerabilities in oncogenic RAS. Read More

Adv Cancer Res 2022 3;153:205-236. Epub 2021 Aug 3.

Department of Medicine, Division of Hematology and Oncology, and The Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, United States. Electronic address:

The non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) is a critical component of RAS/MAPK signaling by acting upstream of RAS to promote oncogenic signaling and tumor growth. Over three decades, SHP2 was considered "undruggable" because enzymatic active-site inhibitors generally showed off-target inhibition of other proteins and low membrane permeability. More recently, allosteric SHP2 inhibitors with striking inhibitory potency have been developed. Read More

Adv Cancer Res 2022 15;153:169-203. Epub 2021 Sep 15.

Screening, Lead Discovery, Nuvisan ICB GmbH, Berlin, Germany.

RAS proteins play major roles in many human cancers, but programs to develop direct RAS inhibitors so far have only been successful for the oncogenic KRAS mutant G12C. As an alternative approach, inhibitors for the RAS guanine nucleotide exchange factor SOS1 have been investigated by several academic groups and companies, and major progress has been achieved in recent years in the optimization of small molecule activators and inhibitors of SOS1. Here, we review the discovery and development of small molecule modulators of SOS1 and their molecular binding modes and modes of action. Read More

Adv Cancer Res 2022 26;153:131-168. Epub 2021 Aug 26.

Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States. Electronic address:

Mutations in the three RAS oncogenes are present in approximately 30% of all human cancers that drive tumor growth and metastasis by aberrant activation of RAS-mediated signaling. Despite the well-established role of RAS in tumorigenesis, past efforts to develop small molecule inhibitors have failed for various reasons leading many to consider RAS as "undruggable." Advances over the past decade with KRAS(G12C) mutation-specific inhibitors have culminated in the first FDA-approved RAS drug, sotorasib. Read More

Adv Cancer Res 2022 2;153:101-130. Epub 2021 Sep 2.

Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. Electronic address:

Mutational activation of the KRAS oncogene is found in ~95% of pancreatic ductal adenocarcinoma (PDAC), the major form of pancreatic cancer. With substantial experimental evidence that continued aberrant KRAS function is essential for the maintenance of PDAC tumorigenic growth, the National Cancer Institute has identified the development of effective anti-KRAS therapies as one of four major initiatives for pancreatic cancer research. The recent clinical success in the development of an anti-KRAS therapy targeting one specific KRAS mutant (G12C) supports the significant potential impact of anti-KRAS therapies. Read More

Adv Cancer Res 2022 14;153:1-27. Epub 2021 Sep 14.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States; Frederick National Laboratory for Cancer Research, Frederick, MD, United States. Electronic address:

In this review, I provide a brief history of the discovery of RAS and the GAPs and GEFs that regulate its activity from a personal perspective. Much of this history has been driven by technological breakthroughs that occurred concurrently, such as molecular cloning, cDNA expression to analyze RAS proteins and their structures, and application of PCR to detect mutations. I discuss the RAS superfamily and RAS proteins as therapeutic targets, including recent advances in developing RAS inhibitors. Read More

Adv Cancer Res 2021 16;152:67-102. Epub 2021 Jun 16.

Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States; Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, United States; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States; Department of Oral and Craniofacial Molecular Biology, School of Dentistry, Virginia Commonwealth University, Richmond, VA, United States; Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, VA, United States. Electronic address:

Head and neck cancers are a heterogeneous, aggressive and genetically complex collection of malignancies of the oral cavity, nasopharynx, oropharynx, hypopharynx, larynx, paranasal sinuses and salivary glands, which are difficult to treat. About 90% of all head and neck cancers are squamous cell carcinomas (HNSCC). Larynx and Oral cavity carcinomas are generally related with tobacco consumption, alcohol abuse (or both), but pharynx carcinomas are generally associated with infection of human papillomavirus (HPV), especially HPV-16 subtype. Read More

Adv Cancer Res 2021 20;152:383-413. Epub 2021 Apr 20.

Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States.

Reductive stress is defined as a condition characterized by excess accumulation of reducing equivalents (e.g., NADH, NADPH, GSH), surpassing the activity of endogenous oxidoreductases. Read More

Adv Cancer Res 2021 16;152:329-381. Epub 2021 Jun 16.

Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States. Electronic address:

An array of human cancers, including hepatocellular carcinoma (HCC), overexpress the oncogene Astrocyte elevated gene-1 (AEG-1). It is now firmly established that AEG-1 is a key driver of carcinogenesis, and enhanced expression of AEG-1 is a marker of poor prognosis in cancer patients. In-depth studies have revealed that AEG-1 positively regulates different hallmarks of HCC progression including growth and proliferation, angiogenesis, invasion, migration, metastasis and resistance to therapeutic intervention. Read More

Adv Cancer Res 2021 28;152:305-327. Epub 2021 Apr 28.

Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

Cisplatin has been a mainstay of cancer chemotherapy since the 1970s. Despite its broad anticancer potential, its clinical use has regularly been constrained by kidney toxicities. This review details those biochemical pathways and metabolic conversions that underlie the kidney toxicities. Read More

Adv Cancer Res 2021 8;152:263-303. Epub 2021 Jul 8.

Department of Cell and Molecular Pharmacology & Experimental Therapeutics, College of Medicine, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

Protein Tyrosine Phosphatases reverse cellular signals initiated by growth factors receptors and other tyrosine kinases by dephosphorylating phosphotyrosine on target proteins. The activity of these enzymes is crucial for maintaining cell homeostasis, yet these enzymes have been often dismissed as humble house-keeping proteins. Understandably, mutations and changes in expression patterns of Protein Tyrosine Phosphatases are implicated in tumorigenesis and various carcinomas. Read More

Adv Cancer Res 2021 1;152:225-262. Epub 2021 Jul 1.

Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Inhibitor of growth family member 4 (ING4) is best known as a tumor suppressor that is frequently downregulated, deleted, or mutated in many cancers. ING4 regulates a broad array of tumor-related processes including proliferation, apoptosis, migration, autophagy, invasion, angiogenesis, DNA repair and chromatin remodeling. ING4 alters local chromatin structure by functioning as an epigenetic reader of H3K4 trimethylation histone marks (H3K4Me3) and regulating gene transcription through directing histone acetyltransferase (HAT) and histone deacetylase (HDAC) protein complexes. Read More

Adv Cancer Res 2021 4;152:205-223. Epub 2021 May 4.

Department of Pharmaceutical & Administrative Sciences, School of Pharmacy, University of Charleston, Charleston, WV, United States. Electronic address:

DNA methylation is an epigenetic modification that contributes to essential biological processes such as retrotransposon silencing, cell differentiation, genomic imprinting and X-chromosome inactivation. DNA methylation generates a stable epigenetic mark associated with silencing of gene expression. Aberrant DNA methylation is associated with the development of different tumor types. Read More

Adv Cancer Res 2021 20;152:179-204. Epub 2021 Apr 20.

Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, Lewisburg, WV, United States. Electronic address:

Introduction: Heat shock proteins (HSPs) constitute a large family of proteins involved in protein folding and maturation. HSP expression is induced by heat shock or other stressors including cellular damage and hypoxia. The major groups, which are classified based on their molecular weight, include HSP27, HSP40, HSP60, HSP70, HSP90, and large HSP (HSP110 and glucose-regulated protein 170). Read More

Adv Cancer Res 2021 12;152:103-177. Epub 2021 Jul 12.

Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States. Electronic address:

Metabolism is an important part of tumorigenesis as well as progression. The various cancer metabolism pathways, such as glucose metabolism and glutamine metabolism, directly regulate the development and progression of cancer. The pathways by which the cancer cells rewire their metabolism according to their needs, surrounding environment and host tissue conditions are an important area of study. Read More

Adv Cancer Res 2021 21;152:1-66. Epub 2021 Jun 21.

Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States. Electronic address:

The enzyme acetylcholinesterase (AChE) is a serine hydrolase whose primary function is to degrade acetylcholine (ACh) and terminate neurotransmission. Apart from its role in synaptic transmission, AChE has several "non-classical" functions in non-neuronal cells. AChE is involved in cellular growth, apoptosis, drug resistance pathways, response to stress signals and inflammation. Read More