Tumor biomarkers for diagnosis, prognosis and targeted therapy

Abstract

Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

Fig. 1

Timeline of the history of tumor biomarker

Fig. 2

Technologies for the detection of tumor biomarkers

Fig. 3

Overview of human tumor biomarkers

Fig. 4

The 14 cancer hallmarks-based biomarkers. Fourteen major characteristics of tumor cells have been proven so far, which have been divided into acquired hallmarks including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, enabling hallmarks including genome instability and mutation, tumor-promoting inflammation, nonmutational epigenetic reprogramming, and polymorphic microbiomes, and emerging hallmarks including deregulating cellular metabolism, avoiding immune destruction, unlocking phenotypic plasticity, and senescent cells. Each of the cancer hallmarks is involved in numerous essential biomarkers that play vital roles in tumor progression

Fig. 5

The cancer invasion and metastasis and its targeted therapy. The tumor metastasis process consists of multiple steps. Initially, tumor cells invade the surrounding stroma and extracellular matrix from the primary tumor site, and then intravasate into the bloodstream or the lymphatics. Subsequently, tumor cells arrest in the circulation and arrive at distant organ sites, followed by extravasating and invading the parenchyma of distant tissues. Finally, tumor cells adapt to the new microenvironment and grow to form metastatic colonization. EMT is the basic embryonic developmental process that transforms polarized non-motile epithelial cells into motile and invasive mesenchymal cells. Multiple cellular stress conditions including hypoxia, inflammation, metabolic stress, and signaling cascades, can induce the expression of EMT transcription factors and prompt tumor metastasis. Meanwhile, MET amplification and mutation, the transcriptional dysregulation of c-MET, degradation deficiency, and abnormal HGF production result in the abnormal expression of HGF/c-MET and tumor progression. Various inhibitors including MMP inhibitors and HGF/c-MET inhibitors have been developed and emerging as promising tools in the suppression of tumor metastasis. c-MET mesenchymal-epithelial transition factor, EMT epithelial-mesenchymal transition, HGF hepatocyte growth factor, MMPs matrix metalloproteinases

Fig. 6

The potential inhibitors that target cancer metabolic process. Glucose is taken up into the cell by glucose transporters GLUT1/4 and phosphorylated by hexokinases HK1 and HK2. Glucose 6-phosphate (P) and its downstream intermediates can either be converted to pyruvate or fuel biosynthesis through different pathways, such as the pentose phosphate pathway which provides ribose 5-P for nucleotide synthesis. Fructose-6-P is involved in the hexosamine biosynthesis pathway. Glycerol 3-P production contributes to the serine and glycine biosynthesis pathways which are regulated by the key enzymes PHGDH and SHMT1/2. Moreover, serine biosynthesis plays an essential role in amino acid metabolism and nucleotide metabolism by regulating one-carbon metabolism which is mediated by the methylenetetrahydrofolate dehydrogenase MTHFD1. Pyruvate can be converted to lactate by LDH and exported through the monocarboxylate transporter MCT-1. Besides, pyruvate can enter the TCA cycle as acetyl-CoA through the mitochondrial pyruvate carrier and pyruvate dehydrogenase. Various pathways influence the production of the mitochondrial acetyl-CoA, including fatty acid β-oxidation, glucose metabolism, and other sources that can condense with oxaloacetate to form citrate, which can then be exported from the mitochondrion. Citrate via ACLY is a vital source of cytoplasmic acetyl-CoA which forms malonyl-CoA by acetyl-CoA carboxylase ACC1 and ACC2. Subsequently, malonyl-CoA is cyclically extended by the addition of carbons from acetyl-CoA by FASN to make saturated fatty acids. Fatty acid catabolism is initiated with the formation of fatty acyl-CoA which is then converted by CPT1 to an acylcarnitine. Pyrimidine synthesis, a multistep process regulated by key enzymes such as CAD and DHODH, can produce pyrimidine nucleotides from glutamine, carbonate, and aspartate. Meanwhile, glutamine is taken up by transporters SLC1A5. Glutamate produced from glutamine by glutaminase enzymes can be used in glutathione synthesis. In addition, the complex V (ATP synthase) and the electron transport chain consisting of four complexes including complex I/II/III/IV (CI–IV), are promising targets for drug development. Inhibitors (red), key enzymes or transporters (blue), and key metabolites (purple) are shown. ACC acetyl-CoA carboxylase, ACLY ATP-citrate lyase, BP bisphosphate, CAD carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase, CoA coenzyme A, CI–IV, complex I/II/III/IV, CV complex V, CPT1 carnitine palmitoyltransferase 1, DHODH dihydroorotate dehydrogenase, FASN fatty acid synthase, GLUT1/GLUT4 glucose transporter 1/4, HK hexokinase, IDH1 isocitrate dehydrogenase 1, LDHA/B lactate dehydrogenase A/B, MCT-1 monocarboxylate transporter 1, MTHFD1 methylenetetrahydrofolate dehydrogenase 1, P phosphate, PHGDH phosphoglycerate dehydrogenase, PKM2 pyruvate kinase M2, SHMT serine hydroxymethyl transferase, SLC1A5 solute carrier family 1 member 5, TCA tricarboxylic acid