Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance.

Cancer is a complex disease displaying a variety of cell states and phenotypes. This diversity, known as cancer cell plasticity, confers cancer cells the ability to change in response to their environment, leading to increased tumor diversity and drug resistance. This review explores the intricate landscape of cancer cell plasticity, offering a deep dive into the cellular, molecular, and genetic mechanisms that underlie this phenomenon. Cancer cell plasticity is intertwined with processes such as epithelial-mesenchymal transition and the acquisition of stem cell-like features. These processes are pivotal in the development and progression of tumors, contributing to the multifaceted nature of cancer and the challenges associated with its treatment. Despite significant advancements in targeted therapies, cancer cell adaptability and subsequent therapy-induced resistance remain persistent obstacles in achieving consistent, successful cancer treatment outcomes. Our review delves into the array of mechanisms cancer cells exploit to maintain plasticity, including epigenetic modifications, alterations in signaling pathways, and environmental interactions. We discuss strategies to counteract cancer cell plasticity, such as targeting specific cellular pathways and employing combination therapies. These strategies promise to enhance the efficacy of cancer treatments and mitigate therapy resistance. In conclusion, this review offers a holistic, detailed exploration of cancer cell plasticity, aiming to bolster the understanding and approach toward tackling the challenges posed by tumor heterogeneity and drug resistance. As articulated in this review, the delineation of cellular, molecular, and genetic mechanisms underlying tumor heterogeneity and drug resistance seeks to contribute substantially to the progress in cancer therapeutics and the advancement of precision medicine, ultimately enhancing the prospects for effective cancer treatment and patient outcomes.

In Silico Investigation of AKT2 Gene and Protein Abnormalities Reveals Potential Association with Insulin Resistance and Type 2 Diabetes.

Type 2 diabetes (T2D) develops from insulin resistance (IR) and the dysfunction of pancreatic beta cells. The AKT2 protein is very important for the protein signaling pathway, and the non-synonymous SNP (nsSNPs) in AKT2 gene may be associated with T2D. nsSNPs can result in alterations in protein stability, enzymatic activity, or binding specificity. The objective of this study was to investigate the effect of nsSNPs on the AKT2 protein structure and function that may result in the induction of IR and T2D. The study identified 20 variants that were considered to be the most deleterious based on a range of analytical tools included (SIFT, PolyPhen2, Mut-pred, SNAP2, PANTHER, PhD-SNP, SNP&Go, MUpro, Cosurf, and I-Mut). Two mutations, p.A179T and p.L183Q, were selected for further investigation based on their location within the protein as determined by PyMol. The results indicated that mutations, p.A179T and p.L183Q alter the protein stability and functional characteristics, which could potentially affect its function. In order to conduct a more in-depth analysis of these effects, a molecular dynamics simulation was performed for wildtype AKT2 and the two mutants (p.A179T and p.L183Q). The simulation evaluated various parameters, including temperature, pressure, density, RMSD, RMSF, SASA, and Region, over a period of 100 ps. According to the simulation results, the wildtype AKT2 protein demonstrated higher stability in comparison to the mutant variants. The mutations p.A179T and p.L183Q were found to cause a reduction in both protein stability and functionality. These findings underscore the significance of the effects of nsSNPs (mutations p.A179T and p.L183Q) on the structure and function of AKT2 that may lead to IR and T2D. Nevertheless, they require further verifications in future protein functional, protein-protein interaction, and large-scale case-control studies. When verified, these results will help in the identification and stratification of individuals who are at risk of IR and T2D for the purpose of prevention and treatment.

Genetic Effects of Vascular Endothelial Growth Factor A (VEGF-A) and Its Association with Disease Progression in Breast Cancer Population of Saudi Arabia.

AIM: Previous studies have shown that vascular endothelial growth factor (VEGFA) gene variants were associated with breast cancer risk. The goal of the current study was to evaluate the genetic effects of the vascular endothelial growth factor (VEGF) on the risk of breast cancer and its association with disease progression. METHODOLOGY: This case control study was conducted on 110 Breast cancer cases and 110 gender matched healthy controls. Vascular endothelial growth factor A (VEGF-A) 1 (-460T>C) genotyping was performed using Amplification refractory mutation system PCR method. The vascular endothelial growth factor A (VEGF-A) (-460T>C) genotypes were collated with different clinicopathological features of breast cancer patients. RESULTS: A significant difference was observed between the genotype distribution of VEGF-A (-460T>C) among breast cancer cases and gender matched healthy controls (p=0.006). The frequencies of all three genotypes CC,CT,TT reported in the breast cancer patients and sex matched healthy controls were  4.54%, 46.36% ,49.20%  and 7.27%, 64.54%, 28.18% respectively. The increased susceptibility to breast cancer disease was found to be associated with VEGF (-460T>C) CC vs TT variant in codominant inheritance model OR 2.78 (0.83-9.26) RR 1.68(1.01 to 2.81) P=0.04. A significant association was reported with VEGF (-460T>C) (CC+CT vs. TT) variant in recessive inheritance model, (OR=2.45 (95% CI= (1.40-4.29), P=0.003. Our findings indicated that VEGF (-460T>C) TT genotype is associated with an increased susceptibility to breast cancer disease. Our result indicates a potential dominant effect of VEGF (-460T>C) TT genotype on susceptibility to the breast cancer disease. CONCLUSION: VEGF (-460T>C) TT genotype significantly increased the risk of breast cancer. VEGF-A (-460T>C) genetic ariability was significantly associated with distant metastasis of the disease. It may be a useful as predisposing genetic marker for breast cancer .Further studies with larger sample sizes are necessary to confirm our findings.
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A huge phyllodes tumor in the breast: a case report.

Phyllodes tumor is a benign breast cancer with a malignant potential. It is very rare in Saudi Arabia and also rare around the world. Malignant phyllodes tumors originate from the connective tissue of the breast, so they are histologically sarcomas. We report the largest phyllodes tumor ever seen in Saudi Arabia, a 41-year-old female who presented with a huge breast mass occupying the whole breast with areas of ulceration. Her history had started 14 months previously with a slowly growing left breast swelling, ultimately the lump ulcerated and became necrotic. Mastectomy with partial resection of the pectoral muscles was done. The tumor specimen measured exactly 30×20×13 cm in size, and weight of 5.4 kg, and with the closest margin of resection 0.5 cm away from the tumor the histopathology report came back as malignant phyllodes tumor. The patient was sent for radiotherapy and chemotherapy. We concluded that accurate preoperative pathological diagnosis is very important for management of phyllodes tumor, and allows correct surgical planning and avoidance of reoperation.