Recently, phage display technology has been announced as the recipient of Nobel Prize in Chemistry 2018. Phage display technique allows high affinity target-binding peptides to be selected from a ...complex mixture pool of billions of displayed peptides on phage in a combinatorial library and could be further enriched through the biopanning process; proving to be a powerful technique in the screening of peptide with high affinity and selectivity. In this review, we will first discuss the modifications in phage display techniques used to isolate various cancer-specific ligands by in situ, in vitro, in vivo, and ex vivo screening methods. We will then discuss prominent examples of solid tumor targeting-peptides; namely peptide targeting tumor vasculature, tumor microenvironment (TME) and overexpressed receptors on cancer cells identified through phage display screening. We will also discuss the current challenges and future outlook for targeting peptidebased therapeutics in the clinics.
Understanding the intratumoral heterogeneity of hepatocellular carcinoma is instructive for developing personalized therapy and identifying molecular biomarkers. Here we applied whole-exome ...sequencing to 69 samples from 11 patients to resolve the genetic architecture of subclonal diversification. Spatial genomic diversity was found in all 11 hepatocellular carcinoma cases, with 29% of driver mutations being heterogeneous, including TERT, ARID1A, NOTCH2, and STAG2. Similar with other cancer types, TP53 mutations were always shared between all tumor regions, that is, located on the "trunk" of the evolutionary tree. In addition, we found that variants within several drug targets such as KIT, SYK, and PIK3CA were mutated in a fully clonal manner, indicating their therapeutic potentials for hepatocellular carcinoma. Temporal dissection of mutational signatures suggested that mutagenic processes associated with exposure to aristolochic acid and aflatoxin might play a more important role in early, as opposed to late, stages of hepatocellular carcinoma development. Moreover, we observed extensive intratumoral epigenetic heterogeneity in hepatocellular carcinoma based on multiple independent analytical methods and showed that intratumoral methylation heterogeneity might play important roles in the biology of hepatocellular carcinoma cells. Our results also demonstrated prominent heterogeneity of intratumoral methylation even in a stable hepatocellular carcinoma genome. Together, these findings highlight widespread intratumoral heterogeneity at both the genomic and epigenomic levels in hepatocellular carcinoma and provide an important molecular foundation for better understanding the pathogenesis of this malignancy.
.
Delivery of small interfering RNA (siRNA) by nanocarriers has shown promising therapeutic potential in cancer therapy. However, poor understanding of the correlation between the physicochemical ...properties of nanocarriers and their interactions with biological systems has significantly hindered its anticancer efficacy. Herein, in order to identify the optimal size of nanocarriers for siRNA delivery, different sized cationic micellar nanoparticles (MNPs) (40, 90, 130, and 180 nm) are developed that exhibit similar siRNA binding efficacies, shapes, surface charges, and surface chemistries (PEGylation) to ensure size is the only variable. Size‐dependent biological effects are carefully and comprehensively evaluated through both in vitro and in vivo experiments. Among these nanocarriers, the 90 nm MNPs show the optimal balance of prolonged circulation and cellular uptake by tumor cells, which result in the highest retention in tumor cells. In contrast, larger MNPs are rapidly cleared from the circulation and smaller MNPs are inefficiently taken up by tumor cells. Accordingly, 90 nm MNPs carrying polo‐like kinase 1 (Plk1)‐specific siRNA (siPlk1) show superior antitumor efficacy, indicating that 90 nm could either be the optimal size for systemic delivery of siRNA or close to it. Our findings provide valuable information for rationally designing nanocarriers for siRNA‐based cancer therapy in the future.
To investigate the optimal size of nanocarriers for siRNA delivery, different sized MNP/siRNAs are rationally designed. Size‐dependent biological effects on circulation, internalization, retention, and overall antitumor efficacy are carefully and comprehensively evaluated. These results indicate that 90 nm could be at or close to the optimal size for systemic delivery of siRNA.
Combination of two or more therapeutic strategies with different mechanisms can cooperatively prohibit cancer development. Combination of chemotherapy and small interfering RNA (siRNA)-based therapy ...represents an example of this approach. Hypothesizing that the chemotherapeutic drug and the siRNA should be simultaneously delivered to the same tumoral cell to exert their synergistic effect, the development of delivery systems that can efficiently encapsulate two drugs and successfully deliver payloads to targeted sites via systemic administration has proven to be challenging. Here, we demonstrate an innovative “two-in-one” micelleplex approach based on micellar nanoparticles of a biodegradable triblock copolymer poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) to systemically deliver the siRNA and chemotherapeutic drug. We show clear evidence that the micelleplex is capable of delivering siRNA and paclitaxel simultaneously to the same tumoral cells both in vitro and in vivo. We further demonstrate that systemic administration of the micelleplex carrying polo-like kinase 1 (Plk1) specific siRNA and paclitaxel can induce a synergistic tumor suppression effect in the MDA-MB-435s xenograft murine model, requiring a thousand-fold less paclitaxel than needed for paclitaxel monotherapy delivered by the micelleplex and without activation of the innate immune response or generation of carrier-associated toxicity.
Intrinsic resistance to anti-HER2 therapy in breast cancer remains an obstacle in the clinic, limiting its efficacy. However, the biological basis for intrinsic resistance is poorly understood. Here ...we performed a CRISPR/Cas9-mediated loss-of-function genetic profiling and identified TALDO1, which encodes the rate-limiting transaldolase (TA) enzyme in the non-oxidative pentose phosphate pathway, as essential for cellular survival following pharmacological HER2 blockade. Suppression of TA increases cell susceptibility to HER2 inhibition in two intrinsically resistant breast cancer cell lines with HER2 amplification. Mechanistically, TA depletion combined with HER2 inhibition significantly reduces cellular NADPH levels, resulting in excessive ROS production and deficient lipid and nucleotide synthesis. Importantly, higher TA expression correlates with poor response to HER2 inhibition in a breast cancer patient cohort. Together, these results pinpoint TA as a novel metabolic enzyme possessing synthetic lethality with HER2 inhibition that can potentially be exploited as a biomarker or target for combination therapy.
This study explored variations in the rhizosphere microbial community composition resulting from the continuous cropping of sorghum. We explored the potential growth-promoting effects of
Bacillus ...amyloliquefaciens
in manipulating the microbial community composition of the rhizosphere soil under continuous cropping. Illumina MiSeq sequencing was used to compare the composition of the bacterial and fungal communities in the rhizosphere soil from a sorghum–maize rotation system, sorghum continuous cropping system, and sorghum continuous cropping with the application of the biological agent
B. amyloliquefaciens
. The rhizosphere soil under continuous sorghum cropping had lower bacterial richness and higher fungal diversity than the sorghum–maize rotation rhizosphere soil. The bacterial phyla Acidobacteria and Gemmatimonadetes, and the fungal phylum Basidiomycota, were strongly enriched in the continuous cropping soil. The class Tremellomycetes was the most dominant group, accounting for 19.30% of the total fungal sequences in the continuous cropping soil and 4.51% in sorghum-maize rotation soil. Application of
B. amyloliquefaciens
significantly decreased the abundance of Tremellomycetes by 8.87% in the continuous cropping soil. Our results indicate that the decrease in sorghum growth and yield under continuous cropping are in coincidence with the alteration of soil microbial community composition, particularly the accumulation of Tremellomycetes in the continuously cropped rhizosphere soil. Our findings contribute to an improved understanding of the effects of continuous sorghum cropping on soil microbiome, and
B. amyloliquefaciens
can be used to manipulate the microbial communities of the sorghum rhizosphere soil.
The group evaluated the relevant evidence using the grading of recommendations assessment, development, and evaluation system, and developed a Clinical Practice Guideline for BCS in Patients with ...Early-Stage Breast Cancer (Version 2021), with the aim of providing guidance on clinical practice to breast surgeons in China. According to results of the long-term follow-up that lasted 20 years, it was found that disease-free survival, metastasis-free survival, and overall survival did not differ significantly between the three arms. The result of Early Breast Cancer Trialists’ Collaborative Group meta-analysis revealed that neoadjuvant chemotherapy can significantly increase the BCS rate. The panel members considered that, in clinical practice, it is not always easy to accurately measure the degree of shrinkage of a tumor after neoadjuvant chemotherapy. ...there was a lack of consensus in the panel regarding the optimal extent of surgery in patients with breast cancer who have received neoadjuvant chemotherapy.
Rhizosphere microbiota play a pivotal role in promoting plant growth and defending against pathogens, but their responses to abiotic environmental stress remain largely elusive. Here, we investigated ...the influences of low-N stress on rhizosphere bacteria of six sorghum cultivars in a glasshouse experiment. The alpha diversity of bacteria (as revealed by Shannon diversity and Chao1 richness indices) was remarkably lower in rhizosphere soils than in bulk soils, and was significantly higher under low-N stress than under N addition. Principal coordinates analysis revealed that the bacterial community compositions in rhizosphere soils were clearly separated from bulk soils, and the rhizosphere soils under low-N stress or with N fertilization were clearly separated, indicating that both rhizosphere effects and N fertilization impacted the rhizosphere bacterial community. Notably, the relative abundances of beneficial bacteria such as Bacillaceae and Streptomycetaceae significantly increased in rhizosphere soils under low-N stress, which had significantly positive correlations with the sorghum N uptake. The relative abundance of Nitrosomonadaceae in rhizosphere soils was significantly lower than that in bulk soils, while the relative abundance of Rhizobiaceae showed an opposite pattern. Taken together, our results suggested that sorghum rhizosphere effects can reduce soil bacterial diversity possibly through recruiting specific bacterial species under low N stress.
Display omitted
•Rhizosphere effects reduced the soil bacterial diversity under low N stress.•Rhizosphere effect and N fertilization separated bacterial community compositions of rhizosphere soil.•Beneficial bacteria were significantly enriched in the rhizosphere of sorghum.•Beneficial bacteria have positive correlations with the sorghum N uptake under low-N stress.
The infiltration of tumor-associated macrophages (TAMs) is associated with extensive angiogenesis, which contributes to a poor prognosis in breast cancer. However, anti-angiogenic therapy with ...VEGF-specific monotherapy has been unsuccessful in treating breast cancer, and the molecular mechanisms associated with chemoresistance remain unclear. Here, we investigated whether CCL18, a chemokine produced by TAMs, can stimulate angiogenesis in breast cancer, as well as the underlying mechanisms. Double immunohistochemical staining for CCL18 and CD34/CD31/vWF was performed in 80 breast cancer samples to study the correlation between CCL18+ TAMs and microvascular density (MVD). Cocultures of TAMs with human umbilical vein endothelial cells (HUVECs) were used to model the inflammatory microenvironment, and CCL18-induced angiogenesis was evaluated both in vitro and in vivo. We demonstrated that CCL18+ TAM infiltration positively associated with MVD in breast cancer samples, which was correlated with tumor metastasis and poor prognosis. We confirmed, both in vitro and in vivo, that CCL18 and VEGF synergistically promoted endothelial cell migration and angiogenesis. Conversely, blocking CCL18 or VEGF with neutralizing antibodies synergistically inhibited the promigratory effects of TAMs. Silencing PITPNM3, a putative CCL18 receptor, on the surface of HUVECs abrogated CCL18-mediated promigration and the enhancement of HUVEC tube formation, independently of VEGFR signaling. Moreover, CCL18 exposure induced the endothelial-mesenchymal transformation and activated ERK and Akt/GSK-3β/Snail signaling in HUVECs, thereby contributing to its pro-angiogenic effects. In conclusion, our findings suggest that CCL18 released from TAMs promotes angiogenesis and tumor progression in breast cancer; thus, CCL18 may serve as a novel target for anti-angiogenic therapies.
Abnormal interaction between non-coding RNAs has been demonstrated to be a common molecular event in various human cancers, but its significance and underlying mechanisms have not been well ...documented. RNA-binding proteins (RBPs) are key regulators of RNA transcription and post-transcriptional processing. In this study, we found that RNA-binding protein 24 (RBM24) was frequently downregulated in nasopharyngeal carcinoma (NPC). The restoration of RBM24 expression suppressed NPC cellular proliferation, migration and invasion and impeded metastatic colonization in mouse models. Microarray analyses revealed that miR-25 expression was upregulated by RBM24 expression in NPC cells. Similarly, ectopic miR-25 expression suppressed NPC cellular growth and motility by targeting the pro-oncogenic lncRNA MALAT1, and the knockdown of MALAT1 expression exhibited similar effects as RBM24 restoration in NPC cells. Overall, these findings suggest a novel role of RBM24 as a tumor suppressor. Mechanistically, RBM24 acts at least in part through upregulating the expression of miR-25, which in turn targets MALAT1 for degradation.
PDF
