Impact of Low BMI and Nutritional Status on Quality of Life and Disease Outcome in Breast Cancer Patients: Insights From a Tertiary Cancer Center in India.

This study investigates the impact of Body Mass Index (BMI) on Quality of Life (QoL) and treatment outcomes in breast cancer (BC) patients, particularly focusing on underweight individuals with compromised nutritional status. A nonrandomized prospective study comprising 121 newly diagnosed patients across various BMI categories utilized FACT-B & FACIT-Sp-12 questionnaires. Follow-ups occurred at baseline, during (3rd and 6th), and after (12th month) anthracycline-taxane chemotherapy, either sequentially or concomitantly. Patients with low BMI (<18.5 kg/m2; 53.7%) exhibited significantly poorer QoL, marked by compromised nutritional indicators (low MUAC and SFT). Repeated measures ANOVA identified significant correlations between BMI groups in functional, social, and emotional QoL aspects (p < 0.05), with no notable differences in other domains. A Chi-square (ꭓ2) test underscored a significant link between BMI and treatment response (p < 0.0001), showing higher rates of non-responders among underweight patients (p = 4.259e-14). The study advocates pretreatment consultation with a dietitian as standard care for Indian BC patients, offering complimentary nutritional support for improved QoL outcomes and treatment responses.

Emerging Futuristic Targeted Therapeutics: A Comprising Study Towards a New Era for the Management of TNBC.

Triple-negative breast cancer is characterized by high lethality attributed to factors such as chemoresistance, transcriptomic, and genomic heterogeneity, leading to a poor prognosis and limiting available targeted treatment options. While the identification of molecular targets remains pivotal for therapy involving chemo drugs, the current challenge lies in the poor response rates, low survival rates, and frequent relapses. Despite various clinical investigations exploring molecular targeted therapies in conjunction with conventional chemo treatment, the outcomes have been less than optimal. The critical need for more effective therapies underscores the urgency to discover potent novel treatments, including molecular and immune targets, as well as emerging strategies. This review provides a comprehensive analysis of conventional treatment approaches and explores emerging molecular and immune-targeted therapeutics, elucidating their mechanisms to address the existing obstacles for a more effective management of triple-negative breast cancer.

Lupeol synergizes with 5-fluorouracil to combat c-MET/EphA2 mediated chemoresistance in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is the most elusive subtype of breast cancer that encounters treatment dilemmas owing to the paucity of druggable targets. We found hyperactivation of c-MET and ephrin type-A receptor 2 (EphA2) in patients treated with 5FU driven chemotherapy which correlated with lower disease-free survival. However, silencing of both these genes resulted in a marked decrease in the invasive, migratory, and tumorigenic potential of TNBC cells, indicating that a dual target strategy is actionable. Lupeol is a phytochemical, with potent anticancer efficacy and minimal side effects in preclinical studies. A synergistic strategy with 5FU and Lupeol elicited promising anticancer responses in vitro, in vivo, and in patient-derived ex vivo tumor culture models. This synergistic regimen is effective, even in the presence of HGF, which mechanistically orchestrates the activation of c-MET and EphA2. These data lay the foundation for the clinical validation of this combination therapy for TNBC patients.

Terminally Exhausted CD8+ T Cells Resistant to PD-1 Blockade Promote Generation and Maintenance of Aggressive Cancer Stem Cells.

SIGNIFICANCE: Cross-talk with TTEX CD8+ T cells mediated by the VEGFR2 axis induces aggressive properties in cancer stem cells to promote tumor progression.

Lupeol and Paclitaxel cooperate in hindering hypoxia induced vasculogenic mimicry via suppression of HIF-1α-EphA2-Laminin-5γ2 network in human oral cancer.

Vasculogenic mimicry (VM), defined as an endothelial cell independent alternative mechanism of blood and nutrient supply by dysregulated tumor cells, is associated with poor prognosis in oral squamous cell carcinoma (OSCC). Here we aim to investigate the underlying molecular mechanism of the synergistic effect of phytochemical Lupeol and standard microtubule inhibitor Paclitaxel in reversing the hypoxia induced VM formation in OSCC. The results demonstrated that the hypoxia induced upregulation of HIF-1α led to augmentation of signaling cascade associated with extracellular matrix remodeling and EMT phenotypes that are mechanistically linked to VM. Induction of HIF-1α altered the expression of EMT/CSC markers (E-Cadherin, Vimentin, Snail, Twist and CD133) and enhanced the ability of cell migration/invasion and spheroid formation. Subsequently, the targeted knockdown of HIF-1α by siRNA led to the perturbation of matrigel mediated tube formation as well as of Laminin-5γ2 expression with the down-regulation of VE-Cadherin, total and phosphorylated (S-897) EphA2, pERK1/2 and MMP2. We also observed that Lupeol in association with Paclitaxel resulted to apoptosis and the disruption of VM associated phenotypes in vitro. We further validated the impact of this novel interventional approach in a patient derived tumor explant culture model of oral malignancy. The ex vivo tumor model mimicked the in vitro anti-VM potential of Lupeol-Paclitaxel combination through down-regulating HIF-1α/EphA2/Laminin-5γ2 cascade. Together, our findings elucidated mechanistic underpinning of hypoxia induced Laminin-5γ2 driven VM formation highlighting that Lupeol-Paclitaxel combination may serve as novel therapeutic intervention in perturbation of VM in human OSCC.

Differential promoter usages of PTCH1 and down regulation of HHIP are associated with HNSCC progression.

PURPOSE: The study was aimed to understand the importance of the hedgehog signaling pathway in development of head and neck squamous cell carcinoma (HNSCC). METHODS: The molecular profiles of the key regulatory genes of the pathway were analysed in the adjacent normal epithelium and tumor samples. The findings were validated in HNSCC cell line. RESULTS: In the bioinformatical analysis, severe reduction in the expression of HHIP was evident in the datasets. The protein and mRNA expression studies in our sample pool revealed interplay of various isoforms of PTCH1 gene (PTCH1-1 and 1B) together with high/medium expression of GLI, SHH, SMO and HHIP in the basal/parabasal layers of the normal epithelium. As the disease progressed, severe downregulation of HHIP coupled with upregulation of GLI1 and differential expression pattern of various PTCH1 gene isoform was evident. Promoter methylation analysis of PTCH1 gene revealed the involvement of more than one promoter of PTCH1 in regulating the expression of different isoform of this gene during tumorigenesis. Treating the FaDu cell line with the demethylating agent 5-aza-2'-deoxycytidine reversed the methylation effects of HHIP and PTCH1 and de-activated the pathway. Also, reduced expression of HHIP-AS1 was observed in our sample pool suggesting multiple ways of regulation of the HHIP gene. Lastly, the patients with under expression of HHIP, HHIP-AS1, high expression of GLI1 showed worse five-year over-all survival trend. CONCLUSION: Dynamic promoter switching of PTCH1 and frequent inactivation of HHIP are the key regulatory events of hedgehog pathway activation in HNSCC.

Orchestrated expression of vasculogenic mimicry and laminin-5γ2 is an independent prognostic marker in oral squamous cell carcinoma.

Vasculogenic mimicry (VM), an endothelial cell-independent alternative mechanism of blood supply to the malignant tumour, has long been considered as an adverse prognostic factor in many cancers. The correlation of VM with laminin-5γ2 and the assessment of their harmonized expression as an independent risk factor have not been elucidated yet in oral squamous cell carcinoma (OSCC). CD31/PAS staining stratified 116 clinically diagnosed OSCC specimens into VM+ and VM- cohorts. The expression pattern of laminin-5γ2 and its upstream modulator MMP2 was evaluated by immunohistochemistry and Western blot. The Kaplan-Meier and Cox regression analyses were performed to assess the survival and prognostic implications. The presence of VM demonstrated a significant correlation with the expression of laminin-5γ2 (p < .001) and MMP2 (p < .001). This pattern was mirrored by the significant upregulation of laminin-5γ2 and MMP2 in VM+ cohorts compared with the VM- ones. Furthermore, co-expression of VM and laminin-5γ2 was significantly associated with tumour grade (p = .010), primary tumour size (p < .001), lymph node metastasis (p = .001) and TNM stages (p < .001) but not with patients' age, gender, tobacco and alcohol consumption habit. Vasculogenic mimicry and laminin-5γ2 double-positive cohort displayed a significantly poorer disease-free survival (DFS) and overall survival (OS). Vasculogenic mimicry, laminin-5γ2 and their subsequent dual expression underlie a significant prognostic value for DFS [hazard ratio (HR) = 9.896, p = .028] and OS [HR = 21.401, p = .033] in OSCC patients. Together, our findings imply that VM along with laminin-5γ2 is strongly linked to the malignant progression in OSCC and VM and laminin-5γ2 coordination emerges as a critical prognostic biomarker for OSCC.

RGS5-TGFß-Smad2/3 axis switches pro- to anti-apoptotic signaling in tumor-residing pericytes, assisting tumor growth.

Regulator-of-G-protein-signaling-5 (RGS5), a pro-apoptotic/anti-proliferative protein, is a signature molecule of tumor-associated pericytes, highly expressed in several cancers, and is associated with tumor growth and poor prognosis. Surprisingly, despite the negative influence of intrinsic RGS5 expression on pericyte survival, RGS5highpericytes accumulate in progressively growing tumors. However, responsible factor(s) and altered-pathway(s) are yet to report. RGS5 binds with Gαi/q and promotes pericyte apoptosis in vitro, subsequently blocking GPCR-downstream PI3K-AKT signaling leading to Bcl2 downregulation and promotion of PUMA-p53-Bax-mediated mitochondrial damage. However, within tumor microenvironment (TME), TGFß appeared to limit the cytocidal action of RGS5 in tumor-residing RGS5highpericytes. We observed that in the presence of high RGS5 concentrations, TGFß-TGFßR interactions in the tumor-associated pericytes lead to the promotion of pSmad2-RGS5 binding and nuclear trafficking of RGS5, which coordinately suppressed RGS5-Gαi/q and pSmad2/3-Smad4 pairing. The RGS5-TGFß-pSmad2 axis thus mitigates both RGS5- and TGFß-dependent cellular apoptosis, resulting in sustained pericyte survival/expansion within the TME by rescuing PI3K-AKT signaling and preventing mitochondrial damage and caspase activation. This study reports a novel mechanism by which TGFß fortifies and promotes survival of tumor pericytes by switching pro- to anti-apoptotic RGS5 signaling in TME. Understanding this altered RGS5 signaling might prove beneficial in designing future cancer therapy.

Exposure to chewing tobacco promotes primary oral squamous cell carcinoma and regional lymph node metastasis by alterations of SDF1α/CXCR4 axis.

A high incidence of oral squamous cell carcinoma (OSCC) is observed in South-East Asian countries due to addictions such as chewing tobacco. Local invasion and distant metastases are primary causes of poor prognosis in OSCC. This study aimed to understand the alterations in metastasis biomarkers, such as stromal cell-derived factor-1α (SDF-1 or SDF1α) and its receptor C-X-C chemokine receptor type 4 (CXCR4), in OSCC patient samples that were stratified based on the history of addiction to chewing tobacco. Targeted immunohistochemical staining and Western blotting were performed on primary tumour and metastatic lymph node (LN) tissues in parallel. Overexpression of hepatocyte growth factor (HGF), activated form of its cognate receptor tyrosine kinase, c-Met (p-Met), GRB2-associated-binding protein 1 (Gab1), phospho-protein kinase B (pAkt), nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (COX-2) were observed in primary tumour and metastatic lymph nodes in both chewer and non-chewer cohorts. Variance analysis showed significant positive correlation between them (P < .0001) indicating upregulation of these biomarkers upon ligand-induced activation of c-Met in both tobacco chewers and non-chewers. Significantly higher expressions of SDF1α and CXCR4 were observed in both primary tumours and metastatic lymph nodes of tobacco chewers (P < .0001) and coincided with overexpressed HGF. In contrast, no significant correlation was observed between expression of HGF and that of SDF1α and CXCR4 in non-chewers. Together, our findings provide important insights into the association of HGF/c-Met and the SDF1α/CXCR4 axis in lymph node metastasis and to an aetiological link with the habit of chewing tobacco.

Chewing tobacco may act as a risk factor for dysplastic transformation of squamous cells in Oral leukoplakia- A cytochemistry based approach.

The use of chewing tobacco is a severe risk factor for oral mucosa related diseases including cancer in India as well as USA, although its relationship with Oral Leukoplakia (OL) or related carcinogenicity is still not clear. This work chose two oncogenic pathway proteins- the Epidermal Growth Factor Receptor and the WNT pathway among leukoplakia patients and established their correlation with the individuals' tobacco chewing habit. 89 fresh patients with OL were selected for the work. The samples were classified based on the individual's tobacco chewing habit. The divided samples were then immunostained with antibodies for both of the EGFR as well as WNT pathway proteins. The samples were further classified based on their proliferation status and the expression of these oncoproteins was also observed. In order to compare the cytological data with histological data, 30 OL patients undergoing biopsy were chosen and immunohistological analysis was performed for the same pathways. Results showed overexpressing EGFR and WNT pathway proteins in all OL samples. Structurally atypic cells had a tendency to overexpress these oncoproteins. However the immunocytochemistry data could not confirm any positive effect of chewing tobacco on the OL's proliferative state. Statistical data from the immunfluorescence finally revealed the overexpression of both EGFR and WNT pathway proteins on the proliferative population establishing chewing tobacco as a positive risk factor for the onset of OL. Data from biopsy samples followed the same trend of protein expression seen in the cytological samples. Dysplastic zones showed huge overexpression of EGFR and WNT pathway proteins among tobacco chewers. In conclusion, this is the first time report showing the effect of chewing tobacco on the EGFR and WNT pathway in OL and its possible role as a potential risk factor for its proliferative type.