Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Июнь 18, 2024

Abstract Tumorigenesis is a multistep process, with oncogenic mutations in normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic and expansion tissues, their transformation into cancer remains rare event, indicating presence of additional driver events for progression to an irreversible, highly heterogeneous, invasive lesion. Recently, researchers are emphasizing mechanisms environmental tumor risk factors epigenetic alterations that profoundly influencing early malignant evolution, independently inducing mutations. Additionally, evolution tumorigenesis reflects multifaceted interplay between cell-intrinsic identities various cell-extrinsic exert selective pressures either restrain uncontrolled proliferation or allow specific clones progress tumors. by which induce both intrinsic cellular competency remodel stress facilitate not fully understood. In this review, we summarize genetic, epigenetic, external events, effects on co-evolution transformed cells ecosystem during initiation evolution. A deeper understanding earliest molecular holds promise translational applications, predicting individuals at high-risk developing strategies intercept transformation.

Язык: Английский

---

Methylation across the central dogma in health and diseases: new therapeutic strategies

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Авг. 24, 2023

The proper transfer of genetic information from DNA to RNA protein is essential for cell-fate control, development, and health. Methylation DNA, RNAs, histones, non-histone proteins a reversible post-synthesis modification that finetunes gene expression function in diverse physiological processes. Aberrant methylation caused by mutations or environmental stimuli promotes various diseases accelerates aging, necessitating the development therapies correct disease-driver imbalance. In this Review, we summarize operating system across central dogma, which includes writers, erasers, readers, reader-independent outputs. We then discuss how dysregulation contributes neurological disorders, cancer, aging. Current small-molecule compounds target modifiers show modest success certain cancers. methylome-wide action lack specificity lead undesirable biological effects cytotoxicity, limiting their therapeutic application, especially with monogenic cause different directions changes. Emerging tools capable site-specific manipulation hold great promise solve dilemma. With refinement delivery vehicles, these new are well positioned advance basic research clinical translation field.

Язык: Английский

---

Eph receptors and ephrins in cancer progression

Nature reviews. Cancer, Год журнала: 2023, Номер 24(1), С. 5 - 27

Опубликована: Ноя. 23, 2023

Язык: Английский

---

Short-chain fatty acids in cancer pathogenesis

Cancer and Metastasis Reviews, Год журнала: 2023, Номер 42(3), С. 677 - 698

Опубликована: Июль 11, 2023

Abstract Cancer is a multi-step process that can be viewed as cellular and immunological shift away from homeostasis in response to selected infectious agents, mutations, diet, environmental carcinogens. Homeostasis, which contributes importantly the definition of “health,” maintained, part by production short-chain fatty acids (SCFAs), are metabolites specific gut bacteria. Alteration composition bacteria, or dysbiosis, often major risk factor for some two dozen tumor types. Dysbiosis characterized diminished levels SCFAs stool, presence “leaky gut,” permitting penetration microbes microbial derived molecules (e.g., lipopolysaccharides) through wall, thereby triggering chronic inflammation. attenuate inflammation inhibiting activation nuclear kappa B, decreasing expression pro-inflammatory cytokines such necrosis alpha, stimulating anti-inflammatory interleukin-10 transforming growth beta, promoting differentiation naïve T cells into regulatory cells, down-regulate immune responses immunomodulation. SCFA function epigenetically histone acetyltransferases alter multiple genes activity many signaling pathways Wnt, Hedgehog, Hippo, Notch) contribute pathogenesis cancer. block cancer stem cell proliferation, potentially delaying development relapse targeting mutated tumors epidermal receptor, hepatocyte factor, MET) suppressors up-regulating PTEN p53). When administered properly, have advantages compared probiotic bacteria fecal transplants. In carcinogenesis, toxic against but not surrounding tissue due differences their metabolic fate. Multiple hallmarks also targets SCFAs. These data suggest may re-establish without overt toxicity either delay prevent various

Язык: Английский

---

The evolution of two transmissible cancers in Tasmanian devils

Science, Год журнала: 2023, Номер 380(6642), С. 283 - 293

Опубликована: Апрель 20, 2023

Tasmanian devils have spawned two transmissible cancer lineages, named devil facial tumor 1 (DFT1) and 2 (DFT2). We investigated the genetic diversity evolution of these clones by analyzing 78 DFT1 41 DFT2 genomes relative to a newly assembled, chromosome-level reference. Time-resolved phylogenetic trees reveal that first emerged in 1986 (1982 1989) 2011 (2009 2012). Subclone analysis documents transmission heterogeneous cell populations. has faster mutation rates than across all variant classes, including substitutions, indels, rearrangements, transposable element insertions, copy number alterations, we identify hypermutated lineage with defective DNA mismatch repair. Several loci show plausible evidence positive selection or DFT2, loss chromosome Y inactivation MGA , but none are common both cancers. This study reveals parallel long-term cancers inhabiting niche devils.

Язык: Английский

---