Tumors are one of the main causes of death in humans. The development of safe and effective methods for early diagnosis and treatment of tumors is a difficult problem that needs to be solved urgently. It is well established that the occurrence of tumors involves complex biological mechanisms, and the tumor microenvironment (TME) plays an important role in regulating the biological behavior of tumors. Cancer-associated fibroblasts (CAFs) are a group of activated fibroblasts with significant heterogeneity and plasticity in the tumor microenvironment. They secrete a variety of active factors to regulate tumor occurrence, development, metastasis, and therapeutic resistance. Although most studies suggest that CAFs have significant tumor-promoting functions, some evidence indicates that they may have certain tumor-suppressive functions in the early stage of tumors. Current research on CAFs continues to face many challenges, and the heterogeneity of their origin, phenotype, and function is a major difficulty and hot spot. To provide new perspectives for the research on CAFs and tumor diagnosis and treatment, this review summarizes the definition, origin, biomarkers, generation mechanism, functions, heterogeneity, plasticity, subpopulations, pre-metastasis niches (PMN), immune microenvironment, and targeted therapy of CAFs, describes the research progress and challenges, and proposes possible future research directions based on existing reports.

Carcinogenesis is a multistep process in which new, parasitic and polymorphic cancer cells evolve from a single, normal diploid cell. This normal cell is converted to a prospective cancer cell, alias "initiated", either by a carcinogen or spontaneously. The initiated cell typically does not have a new distinctive phenotype yet, but evolves spontaneously-over months to decades-to a clinical cancer. The cells of a primary cancer also evolve spontaneously towards more and more malignant phenotypes. The outstanding genotype of initiated and cancer cells is aneuploidy, an abnormal balance of chromosomes, which increases and varies in proportion with malignancy. The driving force of the spontaneous evolution of initiated and cancerous cells to ever more abnormal phenotypes is said to be their "genetic instability". However, since neither the instability of cancer phenotypes nor the characteristically slow kinetics of carcinogenesis are compatible with gene mutation, we propose here that the driving force of carcinogenesis is the inherent instability of aneuploid karyotypes. Aneuploidy renders chromosome structure and segregation errorprone, because it unbalances mitosis proteins and the many teams of enzymes that synthesize and maintain chromosomes. Thus, carcinogenesis is initiated by a random aneuploidy, which is induced either by a carcinogen or spontaneously. The resulting karyotype instability sets off a chain reaction of aneuploidizations, which generate ever more abnormal and eventually cancer-specific combinations and rearrangements of chromosomes. According to this hypothesis the many abnormal phenotypes of cancer are generated by abnormal dosages of thousands of aneuploid, but un-mutated genes. Carcinogenesis is a very rare process in which a normal cell is converted to a cancer cell via multiple "steps" or "stages" of cellular evolution, which correspond to various pre-neoplastic and neoplastic phenotypes and genotypes. 1-4 The clinical and biological phenotypes of the multiple steps of carcinogenesis include hyperplasia, dysplasia, abnormal morphology, anaplasia or dedifferentiation, drug-and multi-drug resistance, immortality, altered histocompatibility including even transplantability to some heterologous species and susceptibility to some heterologous viruses, abnormal metabolism, autonomous growth, invasiveness, and metastasis. 1,5-12 Based on various genetic and cytogenetic markers, including structurally altered or marker chromosomes, most cancers are clonal, i.e., derived from a single cell. 3,13-15 However, a minority is polyclonal. 1,16,17 Despite their clonal origin, "the structure and behavior of tumors are determined by numerous, abnormal characters that, within wide limits, are independently variable, capable of highly varied combinations and assortments and liable to independent progression." 18,19 As a result of this "genetic instability" 3 hardly any two cells from a given cancer are ever the same. 1,20-26,62,137 Indeed, the specific karyotypes and phenotypes of individual cancer cells can v...

Rechargeable Li metal batteries (LMBs) have attracted wide attention as promising candidates for the next generation of energystorage systems. However, limited Coulombic efficiency and unregulated dendrite growth restrict its application. Here, we report a kind of electrolyte by introducing fluorinated aromatic diluents into highconcentration electrolytes (HCEs). Unlike other localized HCEs, the fluorinated aromatic diluents pairing with anions promote the formation of a homogeneous and robust solid−electrolyte interphase (SEI), which endows Li metal with an ultrahigh Coulombic efficiency of ∼99.8%. The Li||LiNi 0.8 Co 0.1 Mn 0.1 O 2 battery holds a capacity retention of >80% over 260 cycles even with a thin Li anode (20 μm) and a high cathode loading (3.5 mAh cm −2 ). A 1.8 Ah Li||NMC811 pouch cell with a lean electrolyte delivers an energy density of 340 Wh kg −1 and a stable cycling life over 200 cycles. The designed electrolytes, which benefit from the synergetic effects of anions and diluents on the SEI, pave the way for the next-generation LMBs.

Aneuploidy or chromosome imbalance is the most massive genetic abnormality of cancer cells. It used to be considered the cause of cancer when it was discovered more than 100 years ago. Since the discovery of the gene, the aneuploidy hypothesis has lost ground to the hypothesis that mutation of cellular genes causes cancer. According to this hypothesis, cancers are diploid and aneuploidy is secondary or nonessential. Here we reexamine the aneuploidy hypothesis in view of the fact that nearly all solid cancers are aneuploid, that many carcinogens are nongenotoxic, and that mutated genes from cancer cells do not transform diploid human or animal cells. By regrouping the gene pool-as in speciation-aneuploidy inevitably will alter many genetic programs. This genetic revolution can explain the numerous unique properties of cancer cells, such as invasiveness, dedifferentiation, distinct morphology, and specific surface antigens, much better than gene mutation, which is limited by the conservation of the existing chromosome structure. To determine whether aneuploidy is a cause or a consequence of transformation, we have analyzed the chromosomes of Chinese hamster embryo (CHE) cells transformed in vitro. This system allows (i) detection of transformation within 2 months and thus about 5 months sooner than carcinogenesis and (ii) the generation of many more transformants per cost than carcinogenesis. To minimize mutation of cellular genes, we have used nongenotoxic carcinogens. It was found that 44 out of 44 colonies of CHE cells transformed by benz[a]pyrene, methylcholanthrene, dimethylbenzanthracene, and colcemid, or spontaneously were between 50 and 100% aneuploid. Thus, aneuploidy originated with transformation. Two of two chemically transformed colonies tested were tumorigenic 2 months after inoculation into hamsters. The cells of transformed colonies were heterogeneous in chromosome number, consistent with the hypothesis that aneuploidy can perpetually destabilize the chromosome number because it unbalances the elements of the mitotic apparatus. Considering that all 44 transformed colonies analyzed were aneuploid, and the early association between aneuploidy, transformation, and tumorigenicity, we conclude that aneuploidy is the cause rather than a consequence of transformation.