ELOVL1 is upregulated and promotes tumor growth in hepatocellular carcinoma through regulating PI3K-AKT-mTOR signaling.

Background: The functions of the ELOVLs are mainly involved in the elongation of saturated and polyunsaturated fatty acids, thus influencing the metabolism of fatty acids. Abnormal lipid metabolism may result in NAFLD and NASH, which may lead to cirrhosis and liver cancer. These results suggest that ELOVLs-mediated metabolism might be involved in the development of HCC. The purpose of this study was to study the expression and function of ELOVL1 in human liver cancer. Method: Using TCGA, GEPIA and other databases, we analyzed the relationship between the expression of ELOVL1 and liver cancer. The expression of ELOVL1 was detected by immunohistochemical method and Western blot method in hepatic carcinoma and hepatic carcinoma cells. Then, the effects of ELOVL1 on proliferation, apoptosis and invasion in vitro and in vivo were investigated by means of different methods. Result: Our results indicate that ELOVL1 is more highly expressed in liver cancer than in normal tissues. Survival analysis showed that OS and DSS were shorter in patients with high ELOVL1 expression than in those with low expression. Multivariate Cox analysis further demonstrated that over-expression of ELOVL1 was an independent risk factor for overall survival in HCC. The results of ROC also confirmed the value of ELOVL1 in the diagnosis of liver cancer. The results of KEGG enrichment and GSEA indicate that ELOVL1 is associated with lipid metabolism and NAFLD, as well as PPAR, PI3K-AKT-mTOR. Compared with the control group, it was found that silencing ELOVL1 in Huh7 and HepG2 cells could inhibit the growth of cells, promote the apoptosis and decrease the metastasis and invasion. Changes in ELOVL1 induced cell proliferation and metastasis may be related to PI3K/AKT/mTOR. Low expression of ELOVL1 inhibited the growth of xenograft tumors in hepatocellular carcinoma xenograft model. Conclusion: Our data indicate that the activation of PI3K/AKT/mTOR pathway in HCC may contribute to the promotion of cancer. Thus, ELOVL1 may be a promising therapeutic target for HCC.

Melanoma-associated fibroblasts in tumor-promotion flammation and antitumor immunity: novel mechanisms and potential immunotherapeutic strategies.

Melanoma, renowned for its aggressive behavior and resistance to conventional treatments, stands as a formidable challenge in the oncology landscape. The dynamic and complex interplay between cancer cells and the tumor microenvironment has gained significant attention, revealing Melanoma-Associated Fibroblasts (MAFs) as central players in disease progression. The heterogeneity of MAFs endows them with a dual role in melanoma. This exhaustive review seeks to not only shed light on the multifaceted roles of MAFs in orchestrating tumor-promoting inflammation but also to explore their involvement in antitumor immunity. By unraveling novel mechanisms underlying MAF functions, this review aims to provide a comprehensive understanding of their impact on melanoma development. Additionally, it delves into the potential of leveraging MAFs for innovative immunotherapeutic strategies, offering new avenues for enhancing treatment outcomes in the challenging realm of melanoma therapeutics.

[Hsa-miR-148a-3p promotes malignant behavior of breast cancer cells by downregulating DUSP1].

OBJECTIVE: To investigate the role of Hsa-miR-148a-3p in regulating biological behaviors of breast cancer cells and explore the mechanism. METHODS: TCGA database was used to identify the differential miRNAs and mRNAs in breast cancer, and the protein-protein interaction (PPI) network was constructed using String and Cytoscape to screen the top 10 hub genes and construct the miRNA-TOP10hub network. RT-qPCR was used to detect the expressions of Hsa-miR-148a-3p and DUSP1 in breast cancer tissues and cell lines. The effects of Hsa-miR-148a-3p mimic and inhibitor on proliferation, migration, invasion and apoptosis of MCF-7 cells were analyzed, and luciferase reporter gene experiment was performed to verify the binding of Hsa-miR-148a-3p to DUSP1. The effect of Hsa-miR-148a-3p overexpression on breast cancer cell xenograft growth was evaluated in nude mice. Kaplan-Meier survival curve analysis was used to analyze the survival of the tumor-bearing mice, and the expression level of DUSP1 in the xenografts was detected using immunohistochemistry. RESULTS: A total of 54 differential miRNAs and 799 differential mRNAs were identified in breast cancer; 3716 target genes were intersected with the differential mRNA, resulting in 150 intersected genes. The top 10 hub genes were downregulated in breast cancer tissues in the PPI network. Double luciferase reporter gene experiment confirmed that Hsa-miR-148a-3p was capable of binding to DUSP1. Hsa-miR-148a-3p was up-regulated and DUSP1 was down-regulated significantly in breast cancer tissues and cells (P<0.01). In breast cancer cells, Hsa-miR-148a-3p mimic strongly promoted cell proliferation, migration and invasion and inhibited cell apoptosis (P<0.01). Hsa-miR-148a-3p overexpression obviously promoted xenograft growth in nude mice (P<0.01), shortened survival time of the mice (P<0.01), and reduced the expression of DUSP1 in the xenografts (P<0.01). CONCLUSION: Hsa-miR-148a-3p promotes malignant behavior of breast cancer cells by inhibiting the expression of DUSP1.

Lung cancer associated with combustion particles and fine particulate matter (PM2.5) - The roles of polycyclic aromatic hydrocarbons (PAHs) and the aryl hydrocarbon receptor (AhR).

Air pollution is the leading cause of lung cancer after tobacco smoking, contributing to 20% of all lung cancer deaths. Increased risk associated with living near trafficked roads, occupational exposure to diesel exhaust, indoor coal combustion and cigarette smoking, suggest that combustion components in ambient fine particulate matter (PM2.5), such as polycyclic aromatic hydrocarbons (PAHs), may be central drivers of lung cancer. Activation of the aryl hydrocarbon receptor (AhR) induces expression of xenobiotic-metabolizing enzymes (XMEs) and increase PAH metabolism, formation of reactive metabolites, oxidative stress, DNA damage and mutagenesis. Lung cancer tissues from smokers and workers exposed to high combustion PM levels contain mutagenic signatures derived from PAHs. However, recent findings suggest that ambient air PM2.5 exposure primarily induces lung cancer development through tumor promotion of cells harboring naturally acquired oncogenic mutations, thus lacking typical PAH-induced mutations. On this background, we discuss the role of AhR and PAHs in lung cancer development caused by air pollution focusing on the tumor promoting properties including metabolism, immune system, cell proliferation and survival, tumor microenvironment, cell-to-cell communication, tumor growth and metastasis. We suggest that the dichotomy in lung cancer patterns observed between smoking and outdoor air PM2.5 represent the two ends of a dose-response continuum of combustion PM exposure, where tumor promotion in the peripheral lung appears to be the driving factor at the relatively low-dose exposures from ambient air PM2.5, whereas genotoxicity in the central airways becomes increasingly more important at the higher combustion PM levels encountered through smoking and occupational exposure.

Differential functions of RhoGDIß in malignant transformation and progression of urothelial cell following N-butyl-N-(4-hydmoxybutyl) nitrosamine exposure.

BACKGROUND: Functional role of Rho GDP-dissociation inhibitor beta (RhoGDIß) in tumor biology appears to be contradictory across various studies. Thus, the exploration of the molecular mechanisms underlying the differential functions of this protein in urinary bladder carcinogenesis is highly significant in the field. Here, RhoGDIß expression patterns, biological functions, and mechanisms leading to transformation and progression of human urothelial cells (UROtsa cells) were evaluated following varying lengths of exposure to the bladder carcinogen N-butyl-N-(4-hydmoxybutyl) nitrosamine (BBN). RESULTS: It was seen that compared to expression in vehicle-treated control cells, RhoGDIß protein expression was downregulated after 2-month of BBN exposure, but upregulated after 6-month of exposure. Assessments of cell function showed that RhoGDIß inhibited UROtsa cell growth in cells with BBN for 2-month exposure, whereas it promoted the invasion of cells treated with BBN for 6 months. Mechanistic studies revealed that 2-month of BBN exposure markedly attenuated DNMT3a abundance, and this led to reduced miR-219a promoter methylation, increased miR-219a binding to the RhoGDIß mRNA 3'UTR, and reduced RhoGDIß protein translation. While after 6-mo of BBN treatment, the cells showed increased PP2A/JNK/C-Jun axis phosphorylation and this in turn mediated overall RhoGDIß mRNA transcription and protein expression as well as invasion. CONCLUSIONS: These findings indicate that RhoGDIß is likely to inhibit the transformation of human urothelial cells during the early phase of BBN exposure, whereas it promotes invasion of the transformed/progressed urothelial cells in the late stage of BBN exposure. The studies also suggest that RhoGDIß may be a useful biomarker for evaluating the progression of human bladder cancers.

Role of long pentraxin PTX3 in cancer.

Cancer has become a leading cause of death and disease burden worldwide, closely related to rapid socioeconomic development. However, the fundamental reason is the lack of comprehensive understanding of the mechanism of cancer, accurate identification of preclinical cancer, and effective treatment of the disease. Therefore, it is particularly urgent to study specific mechanisms of cancer and develop effective prediction and treatment methods. Long Pentraxin PTX3 is a soluble pattern recognition molecule produced by various cells in inflammatory sites, which plays a role as a promoter or suppressor of cancer in multiple tumors through participating in innate immune response, neovascularization, energy metabolism, invasion, and metastasis mechanisms. Based on this, this article mainly reviews the role of PTX3 in various cancers.

The role of transcription factor Yin Yang-1 in colorectal cancer.

BACKGROUND: Yin Yang-1 (YY1) is identified as a transcription factor with multiple functions. However, the role of YY1 in tumorigenesis remains controversial and its regulatory effects may depend upon not only cancer types, but also its interacting partners, chromatin structure, and the context in which it acts. It has been detected that YY1 was highly expressed in colorectal cancer (CRC). Intriguingly, many YY1-repressed genes exhibit tumor suppressive potential while YY1 silencing is related to chemotherapy resistance. Therefore, it is crucial to meticulously explore YY1 protein structure and the dynamic alteration of its interactome in each cancer type. This review attempts to describe the structure of YY1, summarize the mechanism that influence the expression level of YY1 and also highlight the recent advances in our understanding of regulatory insights of YY1 functions in CRC. METHODS: Related studies were identified through scoping search of PubMed, Web of science, Scopus and Emhase concerning the terms of "colorectal cancer", colorectal carcinoma" or CRC with "YY1". The retrieval strategy included title, abstract, and keywords with no language limitations. All the included articles were categorized depending on the mechanisms they explored. RESULTS: In total, 170 articles were identified for further screening. After removing the duplication, not relevant outcomes and review articles, 34 were finally included in the review. Among them, 10 articles revealed the reasons of YY1 high expression in CRC, 13 articles explored YY1 function in CRC, and 11 articles fell into both aspects. In addition, we also summarized 10 clinical trials concerning the expression and activity of YY1 in various diseases, which offers a hint for future application. CONCLUSIONS: YY1 is highly expressed in CRC and broadly recognized as an oncogenic factor during the whole course of CRC. Sporadic controversial views are raised in term of CRC treatment, reminding us that future studies should take the influence of therapeutic regimens into concern.

Nitric oxide and hormesis.

This present paper provides an assessment of the occurrence of nitric oxide (NO)-induced hormetic-biphasic dose/concentration relationships in biomedical research. A substantial reporting of such NO-induced hormetic effects was identified with particular focus on wound healing, tumor promotion, and sperm biology, including mechanistic assessment and potential for translational applications. Numerous other NO-induced hormetic effects have been reported, but require more development prior to translational applications. The extensive documentation of NO-induced biphasic responses, across numerous organs (e.g., bone, cardiovascular, immune, intestine, and neuronal) and cell types, suggests that NO-induced biological activities are substantially mediated via hormetic processes. These observations are particularly important because broad areas of NO biology are constrained by the quantitative features of the hormetic response. This determines the amplitude and width of the low dose stimulation, affecting numerous biomedical implications, study design features (e.g., number of doses, dose spacing, sample sizes, statistical power), and the potential success of clinical trials.

Lack of hepatocarcinogenicity of 2,2'-[1,2-ethanediylbis(oxymethylene)]bis-oxirane, 3-hydroxy-2-naphthoic acid, and acetoacetanilide in a medium-term rat liver bioassay.

The carcinogenicity of 2,2'-[1,2-ethanediylbis(oxymethylene)]bis-oxirane (ethylene glycol diglycidyl ether; EGDE), 3-hydroxy-2-naphthoic acid (HNA), and acetoacetanilide (AAA) was investigated using a medium-term rat liver bioassay for an occupational safety assessment. F344 male rats were administered a single intraperitoneal injection of diethylnitrosamine (200 mg/kg body weight (bw)/day) and then starting 2 weeks later, they received EGDE at 6, 20, and 60 mg/kg bw/day, HNA at 20, 60, and 200 mg/kg bw/day, or AAA at 60, 200, and 600 mg/kg bw/day by oral gavage for 6 weeks. The animals in the positive control group received phenobarbital sodium solution (PB, 25 mg/kg bw/day) by oral gavage and those in the negative control group received a vehicle (water/corn oil) during the administration period of test substances in this model. All animals were subjected to two-thirds partial hepatectomy at week 3 and euthanized at week 8. Neither the number nor the area of hepatocellular foci positive for glutathione S-transferase placental form (GST-P) increased in any of the EGDE, HNA, or AAA treated groups. However, the number and area of GST-P-positive foci significantly increased in the positive control group treated with PB. The results indicate that EGDE, HNA, and AAA lack hepatocarcinogenicity in rats.

Tumor-Promoting Activity and Proteomic Profiling of Cisplatin/Oxaliplatin-Derived DAMPs in Cholangiocarcinoma Cells.

Damage-associated molecular patterns (DAMPs) are well recognized as the molecular signature of immunogenic cell death (ICD). The efficacy of drug-induced ICD function may be impacted by the precise ratio between immunostimulatory and immunoinhibitory DAMPs. Tumor-derived DAMPs can activate tumor-expressed TLRs for the promotion of tumor cell motility, invasion, metastatic spread and resistance to chemotherapeutic treatment. Herein, drug-induced DAMPs' expression and their role in tumor progression are utilized as one crucial point of evaluation regarding chemotherapeutic treatment efficacy in our study. Cisplatin and oxaliplatin, the conventional anticancer chemotherapy drugs, are emphasized as a cause of well-known DAMPs' release from cholangiocarcinoma (CCA) cells (e.g., HSP family, S100, CRT and HMGB1), whereby they trigger Akt, ERK and Cyclin-D1 to promote tumor activities. These findings strengthen the evidence that DAMPs are not only involved in immunomodulation but also in tumor promotion. Therefore, DAMP molecules should be considered as either targets of cancer treatment or biomarkers to evaluate treatment efficacy and tumor recurrence.

Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy.

Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many factors, such as nutritional status, energy level, hypoxic conditions, endoplasmic reticulum stress, hormonal stimulation and drugs, and these factors can regulate autophagy both upstream and downstream of the pathway. In cancer, autophagy acts as a double-edged sword depending on the tissue type and stage of tumorigenesis. On the one hand, autophagy promotes tumor progression in advanced stages by stimulating tumor growth. On the other hand, autophagy inhibits tumor development in the early stages by enhancing its tumor suppressor activity. Moreover, autophagy drives resistance to anticancer therapy, even though in some tumor types, its activation induces lethal effects on cancer cells. In this review, we summarize the biological mechanisms of autophagy and its dual role in cancer. In addition, we report the current understanding of autophagy in some cancer types with markedly high incidence and/or lethality, and the existing therapeutic strategies targeting autophagy for the treatment of cancer.

Molecular links between allergy and cancer.

Epidemiologic studies show both positive and negative associations between allergies and cancer. Allergic diseases may protect against tumorigenesis by promoting the immune surveillance, while carcinogenesis may be promoted through inflammatory responses from allergies. Histamine receptor antagonists are the focus of recent cancer studies because of their promising beneficial effect on tumor development. Also, cytokines, particularly IL-4 or IL-33, IgE as well as allergy-related immune cells such as eosinophils can contribute to tumor growth suppression. Depending on cancer types, cancer therapy may be more beneficial when considering combinatorial immunotherapy. In this review, we give an overview on molecular links between allergies and cancer.

Macrophages and Metabolic Reprograming in the Tumor Microenvironment.

Due to the emergence of traditional drug resistance in tumor treatment, the anti-cancer therapies are facing multiple challenges. Immunotherapy, as a new and universal treatment, has been gradually concerned. The macrophages, as an important part of the immune system, play an important role in it. Many studies have shown that immune state is essential in cancer progression and prognosis, rebuilding the architecture and functional orientation of the tumor region. Most tumors are complex ecosystems that change temporally and spatially under the pressure of proliferation, apoptosis, and extension of every cell in the microenvironment. Here, we review how macrophages states can be dynamically altered in different metabolic states and we also focus on the formation of immune exhaustion. Finally, we look forward to the explorations of clinical treatment for immune metabolism process.

cGAS and cancer therapy: a double-edged sword.

Cyclic guanosine monophosphate-adenosine monophosphate adenosine synthetase (cGAS) is a DNA sensor that detects and binds to cytosolic DNA to generate cyclic GMP-AMP (cGAMP). As a second messenger, cGAMP mainly activates the adapter protein STING, which induces the production of type I interferons (IFNs) and inflammatory cytokines. Mounting evidence shows that cGAS is extensively involved in the innate immune response, senescence, and tumor immunity, thereby exhibiting a tumor-suppressive function, most of which is mediated by the STING pathway. In contrast, cGAS can also act as an oncogenic factor, mostly by increasing genomic instability through inhibitory effects on DNA repair, suggesting its utility as an antitumor target. This article reviews the roles and the underlying mechanisms of cGAS in cancer, particularly focusing on its dual roles in carcinogenesis and tumor progression, which are probably attributable to its classical and nonclassical functions, as well as approaches targeting cGAS for cancer therapy.

Environmental exposure and the role of AhR in the tumor microenvironment of breast cancer.

Activation of the aryl hydrocarbon receptor (AhR) through environmental exposure to chemicals including polycyclic aromatic hydrocarbons (PAHs) and polychlorinated dibenzo-p-dioxins (PCDDs) can lead to severe adverse health effects and increase the risk of breast cancer. This review considers several mechanisms which link the tumor promoting effects of environmental pollutants with the AhR signaling pathway, contributing to the development and progression of breast cancer. We explore AhR's function in shaping the tumor microenvironment, modifying immune tolerance, and regulating cancer stemness, driving breast cancer chemoresistance and metastasis. The complexity of AhR, with evidence for both oncogenic and tumor suppressor roles is discussed. We propose that AhR functions as a "molecular bridge", linking disproportionate toxin exposure and policies which underlie environmental injustice with tumor cell behaviors which drive poor patient outcomes.

Cutaneous Malignancies in Tattoos, a Case Series of Six Patients.

BACKGROUND: A variety of side effects following the tattooing of the skin were reported over the years. Analytical studies showed that some tattoo inks contain harmful compounds. METHODS: We presented six patient cases with cutaneous malignancies in tattooed skin and performed an extensive literature research. RESULTS: Two patients with black ink tattoos that were diagnosed with malignant melanoma raises the number of described cases to 36 patients. One of the patients developed an immunologic reaction limited to the tattoo area after treatment with a targeted immune therapy. In the other patient, the malignancy (malignant melanoma) was fatal. Basal cell carcinoma was seen in four patients with tattoos containing varying ink colors (black, green, red). This increased the number of described patient cases to 18. Although some ink components and their cleavage products have carcinogenic properties, epidemiological evidence for a causative correlation fails. Further epidemiologic studies on tattoos and malignancies, as well as on the appearance of naevi in tattoos, are necessary. Determining the type of mutation might be helpful to separate sun-induced tumors from skin cancers due to other pathogenic mechanisms.

Early Diagnostic Ability of Human Complement Factor B in Pancreatic Cancer Is Partly Linked to Its Potential Tumor-Promoting Role.

Although plasma complement factor B (CFB, NX_P00751), both alone and in combination with CA19-9 (i.e., the ComB-CAN), previously exhibited a reliable diagnostic ability for pancreatic cancer (PC), its detectability of the early stages and the cancer detection mechanism remained elusive. We first evaluated the diagnostic accuracy of ComB-CAN using plasma samples from healthy donors (HDs), patients with chronic pancreatitis (CP), and patients with different PC stages (I/II vs III/IV). An analysis of the area under the curve (AUC) by PanelComposer using logistic regression revealed that ComB-CAN has a superior diagnostic ability for early-stage PC (97.1.% [95% confidence interval (CI): (97.1-97.2)]) compared with CFB (94.3% [95% CI: 94.2-94.4]) or CA19-9 alone (34.3% [95% CI: 34.1-34.4]). In the comparisons of all stages of patients with PC vs CP and HDs, the AUC values of ComB-CAN, CFB, and CA19-9 were 0.983 (95% CI: 0.983-0.983), 0.950 (95% CI: 0.950-0.951), and 0.873 (95% CI: 0.873-0.874), respectively. We then investigated the molecular mechanism underlying the detection of early-stage PC by using stable cell lines of CFB knockdown and CFB overexpression. A global transcriptomic analysis coupled to cell invasion assays of both CFB-modulated cell lines suggested that CFB plays a tumor-promoting role in PC, which likely initiates the PI3K-AKT cancer signaling pathway. Thus our study establishes ComB-CAN as a reliable early diagnostic marker for PC that can be clinically applied for early PC screening in the general public.

Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells.

The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis.

Tumor-associated macrophages in cholangiocarcinoma: complex interplay and potential therapeutic target.

Cholangiocarcinoma (CCA) is an aggressive and multifactorial malignancy of the biliary tract. The carcinogenesis of CCA is associated with genomic and epigenetic abnormalities, as well as environmental effects. However, early clinical diagnosis and reliable treatment strategies of CCA remain unsatisfactory. Multiple compartments of the tumor microenvironment significantly affect the progression of CCA. Tumor-associated macrophages (TAMs) are a type of plastic immune cells that are recruited and activated in the CCA microenvironment, especially at the tumor invasive front and perivascular sites. TAMs create a favorable environment that benefits CCA growth by closely interacting with CCA cells and other stromal cells via releasing multiple protumor factors. In addition, TAMs exert immunosuppressive and antichemotherapeutic effects, thus intensifying the malignancy. Targeting TAMs may provide an improved understanding of, and novel therapeutic approaches for, CCA. This review focuses on revealing the interplay between TAMs and CCA.

Thresholds for carcinogens.

Current regulatory cancer risk assessment principles and practices assume a linear dose-response relationship-the linear no-threshold (LNT) model-that theoretically estimates cancer risks occurring following low doses of carcinogens by linearly extrapolating downward from experimentally determined risks at high doses. The two-year rodent bioassays serve as experimental vehicles to determine the high-dose cancer risks in animals and then to predict, by extrapolation, the number of carcinogen-induced tumors (tumor incidence) that will arise during the lifespans of humans who are exposed to environmental carcinogens at doses typically orders of magnitude below those applied in the rodent assays. An integrated toxicological analysis is conducted herein to reconsider an alternative and once-promising approach, tumor latency, for estimating carcinogen-induced cancer risks at low doses. Tumor latency measures time-to-tumor following exposure to a carcinogen, instead of tumor incidence. Evidence for and against the concept of carcinogen-induced tumor latency is presented, discussed, and then examined with respect to its relationship to dose, dose rates, and the dose-related concepts of initiation, tumor promotion, tumor regression, tumor incidence, and hormesis. Considerable experimental evidence indicates: (1) tumor latency (time-to-tumor) is inversely related to the dose of carcinogens and (2) lower doses of carcinogens display quantifiably discrete latency thresholds below which the promotion and, consequently, the progression and growth of tumors are delayed or prevented during a normal lifespan. Besides reconciling well with the concept of tumor promotion, such latency thresholds also reconcile favorably with the existence of thresholds for tumor incidence, the stochastic processes of tumor initiation, and the compensatory repair mechanisms of hormesis. Most importantly, this analysis and the arguments presented herein provide sound theoretical, experimental, and mechanistic rationales for rethinking the foundational premises of low-dose linearity and updating the current practices of cancer risk assessment to include the concept of carcinogen thresholds.