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Background Pancreatic adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by aggressive progression, pronounced stromal desmoplasia, and a limited response to targeted therapies. Although epidermal growth factor receptor (EGFR) inhibitors have shown promise in preclinical studies, their clinical efficacy has been modest, suggesting the existence of compensatory signaling networks. Methods An integrated analytical framework was employed, combining bulk transcriptomic analyses of TCGA-PDAC and GTEx datasets, DNA methylation profiling, protein–protein interaction (PPI) network analysis, immune infiltration estimation, and single-cell RNA sequencing. Expression patterns and clinical associations of integrin αvβ3 were evaluated using TCGA, GEPIA, UALCAN, and the Human Protein Atlas. Functional validation was performed using in vitro assays in pancreatic cancer cell lines to assess the effects of DL-N2, a tetrac-conjugated nanoparticle targeting integrin αvβ3, alone or in combination with gefitinib. Results Integrin αvβ3 (ITGAV/ITGB3) was upregulated in PDAC tissues compared with normal pancreatic tissue and was associated with poor prognosis. Single-cell transcriptomic profiling localized αvβ3 expression to malignant ductal cells and stromal fibroblasts. Computational analyses predicted strong associations of αvβ3 with EGFR, MMP2, and MMP9, implicating it in epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and immune regulation. In vitro, experiments showed that DL-N2 suppressed basal and EGF-induced proliferation, decreased the expression of EGFR , PCNA , and CCND1 , and reduced angiogenic and invasive mediators, including VEGF-α , bFGF2 , and MMP9 . Notably, DL-N2 inhibited PD-L1 expression, linking αvβ3 signaling to immune evasion. In addition, both DL-N2 and gefitinib inhibited cell migration, and their combined treatment exerted an additive effect on the suppression of pancreatic cancer cell migration. Conclusion Our findings establish integrin αvβ3 as a multifunctional regulator of pancreatic cancer progression, integrating growth-associated signaling, extracellular matrix regulation, and immune-associated pathways. Targeting αvβ3 with DL-N2 remodels both tumor-intrinsic and microenvironmental pathways, potentially enhancing EGFR inhibition and restoring chemosensitivity. Dual blockade of αvβ3 and EGFR represents a rational therapeutic strategy to overcome drug resistance and improve outcomes in PDAC. Highlights Mechanistic Crosstalk Clarity : Ensure the introduction (which you've drafted well) leads directly to results that prove how integrin αvβ3 and EGFR interact. Mentioning FAK (Focal Adhesion Kinase) as the bridge is a common 2026 reviewer expectation for this pathway. Clinical Relevance : JTM editors look for \"human-centric\" data. If your paper relies on cell lines, ensure you have validated the expression of αvβ3 and EGFR in human PDAC tissue samples or publicly available databases (like TCGA or GTEx) to prove clinical significance. Address “Thyroid Hormone” Implications : Since you mentioned thyroid hormones (T3/T4) binding to αvβ3, reviewers may ask if patients on thyroid medication show different PDAC outcomes. Briefly addressing this \"translational\" clinical potential in your discussion can significantly strengthen your case

The field of thyroid hormone signaling has grown more complex in recent years. In particular, it has been suggested that some thyroid hormone derivatives, tentatively named “novel thyroid hormones” or “active thyroid hormone metabolites”, may act as independent chemical messengers. They include 3,5-diiodothyronine (T2), 3-iodothyronamine (T1AM), and several iodothyroacetic acids, i.e., 3,5,3’,5’-thyroacetic acid (TA4), 3,5,3’-thyroacetic acid (TA3), and 3-thyroacetic acid (TA1). We summarize the present knowledge on these compounds, namely their biosynthetic pathways, endogenous levels, molecular targets, and the functional effects elicited in experimental preparations or intact animals after exogenous administration. Their physiological and pathophysiological role is discussed, and potential therapeutic applications are outlined. The requirements needed to qualify these substances as chemical messengers must still be validated, although promising evidence has been collected. At present, the best candidate to the role of independent chemical messenger appears to be T1AM, and its most interesting effects concern metabolism and brain function. The responses elicited in experimental animals have suggested potential therapeutic applications. TA3 has an established role in thyroid hormone resistance syndromes, and is under investigation in Allen–Herndon–Dudley syndrome. Other potential targets are represented by obesity and dyslipidemia (for T2 and T1AM); dementia and degenerative brain disease (for T1AM and TA1); cancer (for T1AM and TA4). Another intriguing and unexplored question is the potential relevance of these metabolites in the clinical picture of hypothyroidism and in the response to replacement therapy.

A cell surface receptor for thyroid hormone that activates extracellular regulated kinase (ERK) 1/2 has been identified on integrin αvβ3. We have examined the actions of thyroid hormone initiated at the integrin on human NCI-H522 non-small cell lung carcinoma and NCI-H510A small cell lung cancer cells. At a physiologic total hormone concentration (10(-7) M), T(4) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3'-triiodo-L-thyronine (T(3)) at a supraphysiologic concentration. Neutralizing antibody to integrin αvβ3 and an integrin-binding Arg-Gly-Asp (RGD) peptide blocked thyroid hormone-induced PCNA expression. Tetraiodothyroacetic acid (tetrac) lacks thyroid hormone function but inhibits binding of T(4) and T(3) to the integrin receptor; tetrac eliminated thyroid hormone-induced lung cancer cell proliferation and ERK1/2 activation. In these estrogen receptor-α (ERα)-positive lung cancer cells, thyroid hormone (T(4)>T(3)) caused phosphorylation of ERα; the specific ERα antagonist ICI 182,780 blocked T(4)-induced, but not T(3)-induced ERK1/2 activation, as well as ERα phosphorylation, proliferating-cell nuclear antigen (PCNA) expression and hormone-dependent thymidine uptake by tumor cells. Thus, in ERα-positive human lung cancer cells, the proliferative action of thyroid hormone initiated at the plasma membrane is at least in part mediated by ERα. In summary, thyroid hormone may be one of several endogenous factors capable of supporting proliferation of lung cancer cells. Activity as an inhibitor of lung cancer cell proliferation induced at the integrin receptor makes tetrac a novel anti-proliferative agent.

The anti-angiogenic agent, diamino propane tetraiodothyroacetic acid (DAT), is a thyro-integrin (integrin αvβ3) antagonist anticancer agent that works via genetic and nongenetic actions. Tetraiodothyroacetic acid (tetrac) and DAT as thyroid hormone derivatives influence gene expression after they transport across cellular membranes. To restrict the action of DAT to the integrin αvβ3 receptors on the cell surface, we used DAT-conjugated PLGA nanoparticles (NDAT) in an active targeting mode to bind to these receptors. Preparation and characterization of NDAT is described, and both in vitro and in vivo experiments were done to compare DAT to NDAT. Intracellular uptake and distribution of DAT and NDAT in U87 glioblastoma cells were evaluated using confocal microscopy and showed that DAT reached the nucleus, but NDAT was restricted from the nucleus. Pharmacokinetic studies using LC-MS/MS analysis in male C57BL/6 mice showed that administration of NDAT improved the area under the drug concentration curve AUC by 4-fold at a dose of 3 mg/kg when compared with DAT, and C of NDAT (4363 ng/mL) was 8-fold greater than that of DAT (548 ng/mL). Biodistribution studies in the mice showed that the concentrations of NDAT were higher than DAT/Cremophor EL micelles in heart, lung, liver, spleen, and kidney. In another mouse model using female NCr nude homozygous mice with U87 xenografts, tumor growth was significantly decreased at doses of 1 and 3 mg/kg of NDAT. In the chick chorioallantoic membrane (CAM) assay used to measure angiogenesis, DAT (500 ng/CAM) resulted in 48% inhibition of angiogenesis levels. In comparison, NDAT at low dose (50 ng/CAM) showed 45% inhibition of angiogenesis levels. Our investigation of NDAT bridges the study of polymeric nanoparticles and anti-angiogenic agents and offers new insight for the rational design of anti-angiogenic agents.

Background: Heteronemin, a marine sesterterpenoid-type natural product, possesses an antiproliferative effect in cancer cells. In addition, heteronemin has been shown to inhibit p53 expression. Our laboratory has demonstrated that the thyroid hormone deaminated analogue, tetrac, activates p53 and induces antiproliferation in colorectal cancer. However, such drug mechanisms are still to be studied in oral cancer cells. Methods: We investigated the antiproliferative effects by Cell Counting Kit-8 and flow cytometry. The signal transduction pathway was measured by Western blotting analyses. Quantitative PCR was used to evaluate gene expression regulated by heteronemin, 3,3’,5,5’-tetraiodothyroacetic acid (tetrac), or their combined treatment in oral cancer cells. Results: Heteronemin inhibited not only expression of proliferative genes and Homo Sapiens Thrombospondin 1 (THBS-1) but also cell proliferation in both OEC-M1 and SCC-25 cells. Remarkably, heteronemin increased TGF-β1 expression in SCC-25 cells. Tetrac suppressed expression of THBS-1 but not p53 expression in both cancer cell lines. Furthermore, the synergistic effect of tetrac and heteronemin inhibited ERK1/2 activation and heteronemin also blocked STAT3 signaling. Combined treatment increased p53 protein and p53 activation accumulation although heteronemin inhibited p53 expression in both cancer cell lines. The combined treatment induced antiproliferation synergistically more than a single agent. Conclusions: Both heteronemin and tetrac inhibited ERK1/2 activation and increased p53 phosphorylation. They also inhibited THBS-1 expression. Moreover, tetrac suppressed TGF-β expression combined with heteronemin to further enhance antiproliferation and anti-metastasis in oral cancer cells.

The clinical behavior of thyroid cancers is seen to reflect inherent transcriptional activities of mutated genes and trophic effects on tumors of circulating pituitary thyrotropin (TSH). The thyroid hormone, L-thyroxine (T4), has been shown to stimulate proliferation of a large number of different forms of cancer. This activity of T4 is mediated by a cell surface receptor on the extracellular domain of integrin αvβ3. In this brief review, we describe what is known about T4 as a circulating trophic factor for differentiated (papillary and follicular) thyroid cancers. Given T4′s cancer-stimulating activity in differentiated thyroid cancers, it was not surprising to find that genomic actions of T4 were anti-apoptotic. Transduction of the T4-generated signal at the integrin primarily involved mitogen-activated protein kinase (MAPK). In thyroid C cell-origin medullary carcinoma of the thyroid (MTC), effects of thyroid hormone analogues, such as tetraiodothyroacetic acid (tetrac), include pro-angiogenic and apoptosis-linked genes. Tetrac is an inhibitor of the actions of T4 at αvβ3, and it is assumed, but not yet proved, that the anti-angiogenic and pro-apoptotic actions of tetrac in MTC cells are matched by T4 effects that are pro-angiogenic and anti-apoptotic. We also note that papillary thyroid carcinoma cells may express the leptin receptor, and circulating leptin from adipocytes may stimulate tumor cell proliferation. Transcription was stimulated by leptin in anaplastic, papillary, and follicular carcinomas of genes involved in invasion, such as matrix metalloproteinases (MMPs). In summary, thyroid hormone analogues may act at their receptor on integrin αvβ3 in a variety of types of thyroid cancer to modulate transcription of genes relevant to tumor invasiveness, apoptosis, and angiogenesis. These effects are independent of TSH.

The tetraiodothyroacetic acid (tetrac) component of nano-diamino-tetrac (NDAT) is chemically bonded via a linker to a poly(lactic- -glycolic acid) nanoparticle that can encapsulate anticancer drugs. Tetrac targets the plasma membrane of cancer cells at a receptor on the extracellular domain of integrin αvβ3. In this study, we evaluate the efficiency of NDAT delivery of paclitaxel and doxorubicin to, respectively, pancreatic and breast cancer orthotopic nude mouse xenografts. Intra-tumoral drug concentrations were 5-fold (paclitaxel; <0.001) and 2.3-fold (doxorubicin; <0.01) higher than with conventional systemic drug administration. Tumor volume reductions reflected enhanced xenograft drug uptake. Cell viability was estimated by bioluminescent signaling in pancreatic tumors and confirmed an increased paclitaxel effect with drug delivery by NDAT. NDAT delivery of chemotherapy increases drug delivery to cancers and increases drug efficacy.

The aim was to evaluate tetraiodothyroacetic acid (tetrac), a thyroid hormone analog of l-thyroxin, conjugated to poly(lactic- -glycolic acid) nanoparticles (T-PLGA-NPs) both and for the treatment of drug-resistant breast cancer. The uptake of tetrac and T-PLGA-NPs in doxorubicin-resistant MCF7 (MCF7-Dx) cells was evaluated using confocal microscopy. Cell proliferation assays and a chick chorioallantoic membrane model of FGF2-induced angiogenesis were used to evaluate the anticancer effects of T-PLGA-NPs. efficacy was examined in a MCF7-Dx orthotopic tumor BALBc nude mouse model. T-PLGA-NPs were restricted from entering into the cell nucleus, and T-PLGA-NPs inhibited angiogenesis by 100% compared with 60% by free tetrac. T-PLGA-NPs enhanced inhibition of tumor-cell proliferation at a low-dose equivalent of free tetrac. treatment with either tetrac or T-PLGA-NPs resulted in a three- to five-fold inhibition of tumor weight. T-PLGA-NPs have high potential as anticancer agents, with possible applications in the treatment of drug-resistant cancer. Original submitted 2 May 2012; Revised submitted 21 November 2012