The Role of TAM Receptors in Bone Engelmann, Janik; Ragipoglu, Deniz; Ben-Batalla, Isabel ...
International journal of molecular sciences,
12/2023, Letnik:
25, Številka:
1
Journal Article
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The TAM (TYRO3, MERTK, and AXL) family of receptor tyrosine kinases are pleiotropic regulators of adult tissue homeostasis maintaining organ integrity and self-renewal. Disruption of their ...homeostatic balance fosters pathological conditions like autoinflammatory or degenerative diseases including rheumatoid arthritis, lupus erythematodes, or liver fibrosis. Moreover, TAM receptors exhibit prominent cell-transforming properties, promoting tumor progression, metastasis, and therapy resistance in various cancer entities. Emerging evidence shows that TAM receptors are involved in bone homeostasis by regulating osteoblastic bone formation and osteoclastic bone resorption. Therefore, TAM receptors emerge as new key players of the regulatory cytokine network of osteoblasts and osteoclasts and represent accessible targets for pharmacologic therapy for a broad set of different bone diseases, including primary and metastatic bone tumors, rheumatoid arthritis, or osteoporosis.
It is well-known that sex hormones can directly and indirectly influence immune cell function. Different studies support a suppressive role of androgens on different components of the immune system ...by decreasing antibody production, T cell proliferation, NK cytotoxicity, and stimulating the production of anti-inflammatory cytokines. Androgen receptors have also been detected in many different cells of hematopoietic origin leading to direct effects of their ligands on the development and function of the immune system. The immunosuppressive properties of androgens could contribute to gender dimorphisms in autoimmune and infectious disease and thereby also hamper immune surveillance of tumors. Consistently, females generally are more prone to autoimmunity, while relatively less susceptible to infections, and have lower incidence and mortality of the majority of cancers compared to males. Some studies show that androgen deprivation therapy (ADT) can induce expansion of naïve T cells and increase T-cell responses. Emerging clinical data also reveal that ADT might enhance the efficacy of various immunotherapies including immune checkpoint blockade. In this review, we will discuss the potential role of androgens and their receptors in the immune responses in the context of different diseases. A particular focus will be on cancer, highlighting the effect of androgens on immune surveillance, tumor biology and on the efficacy of anti-cancer therapies including emerging immune therapies.
From the original concepts that tumors require a vascular supply to grow and that blocking angiogenesis could suppress tumor growth, the oncology field has witnessed clinical successes of ...VEGF-targeted antiangiogenic medicine. The field is now facing the challenge of overcoming resistance to VEGF-targeted therapy, and therefore additional angiogenesis inhibitors are being developed. Studies on how endothelial 'tip, stalk and phalanx cells' form sprouts have identified promising candidate targets with complementary mechanisms to VEGF. This Review provides a conceptual framework in which molecular discoveries and principles are discussed in light of clinical opportunities to develop new antiangiogenic agents.
Circulating tumor cells (CTCs) hold great potential to answer key questions of how non-small cell lung cancer (NSCLC) evolves and develops resistance upon anti-PD-1/PD-L1 treatment. Currently, their ...clinical utility in NSCLC is compromised by a low detection rate with the established, Food and Drug Administration (FDA)-approved, EpCAM-based CellSearch
System. We tested an epitope-independent method (Parsortix
system) and utilized it to assess PD-L1 expression of CTCs from NSCLC patients. We prospectively collected 127 samples, 97 of which were analyzed with the epitope-independent system in comparison to the CellSearch system. CTCs were determined by immunocytochemistry as intact, nucleated, CD45
, pankeratins (K)
cells. PD-L1 status of CTCs was evaluated from 89 samples. With the epitope-independent system, ≥1 CTC per blood sample was detected in 59 samples (61%) compared to 31 samples (32%) with the EpCAM-based system. Upon PD-L1 staining, 47% of patients harbored only PD-L1
CTCs, 47% had PD-L1
and PD-L1
CTCs, and only 7% displayed exclusively PD-L1
CTCs. The percentage of PD-L1
CTCs did not correlate with the percentage of PD-L1
in biopsies determined by immunohistochemistry (
= 0.179). Upon disease progression, all patients showed an increase in PD-L1
CTCs, while no change or a decrease in PD-L1
CTCs was observed in responding patients (
= 11;
= 0.001). Our data show a considerable heterogeneity in the PD-L1 status of CTCs from NSCLC patients. An increase of PD-L1
CTCs holds potential to predict resistance to PD-1/PD-L1 inhibitors.
Novel antiangiogenic strategies with complementary mechanisms are needed to maximize efficacy and minimize resistance to current angiogenesis inhibitors. We explored the therapeutic potential and ...mechanisms of αPlGF, an antibody against placental growth factor (PlGF), a VEGF homolog, which regulates the angiogenic switch in disease, but not in health. αPlGF inhibited growth and metastasis of various tumors, including those resistant to VEGF(R) inhibitors (VEGF
R
Is), and enhanced the efficacy of chemotherapy and VEGF
R
Is. αPlGF inhibited angiogenesis, lymphangiogenesis, and tumor cell motility. Distinct from VEGF
R
Is, αPlGF prevented infiltration of angiogenic macrophages and severe tumor hypoxia, and thus, did not switch on the angiogenic rescue program responsible for resistance to VEGF
R
Is. Moreover, it did not cause or enhance VEGF
R
I-related side effects. The efficacy and safety of αPlGF, its pleiotropic and complementary mechanism to VEGF
R
Is, and the negligible induction of an angiogenic rescue program suggest that αPlGF may constitute a novel approach for cancer treatment.
The estrogen receptor α (ERα) controls cell proliferation and tumorigenesis by recruiting various cofactors to estrogen response elements (EREs) to control gene transcription. A deeper understanding ...of these transcriptional mechanisms may uncover therapeutic targets for ERα-dependent cancers. We show that BRD4 regulates ERα-induced gene expression by affecting elongation-associated phosphorylation of RNA polymerase II (RNAPII) and histone H2B monoubiquitination. Consistently, BRD4 activity is required for proliferation of ER+ breast and endometrial cancer cells and uterine growth in mice. Genome-wide studies revealed an enrichment of BRD4 on transcriptional start sites of active genes and a requirement of BRD4 for H2B monoubiquitination in the transcribed region of estrogen-responsive genes. Importantly, we demonstrate that BRD4 occupancy on distal EREs enriched for H3K27ac is required for recruitment and elongation of RNAPII on EREs and the production of ERα-dependent enhancer RNAs. These results uncover BRD4 as a central regulator of ERα function and potential therapeutic target.
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•BRD4 regulates estrogen-induced RNAPII p-Ser2 and H2Bub1 in ER+ breast cancers•BRD4 occupies transcriptional start sites and EREs upon estrogen stimulation•BRD4 is required for estrogen-induced transcription and increased cell proliferation•BRD4 regulates enhancer RNA production
Estrogen receptor α (ERα)-dependent cancers are the most common breast cancers among women, and targeting these cancers at the transcriptional level has been an effective therapeutic strategy. Nagarajan at al. demonstrate that BRD4 acts as a coactivator of ERα-stimulated transcription by recruiting RNA polymerase II on promoters and enhancers and affecting enhancer RNA synthesis and, thus, mRNA transcription by affecting transcriptional elongation. Thus, small molecule inhibition of BRD4 can provide a potential therapeutic target for ERα-dependent breast cancers.
In lung cancer, the relevance of various circulating tumour cell (CTC) subgroups in different lung cancer subtypes is unclear. We performed a comprehensive meta-analysis to assess the prognostic ...value of CTCs in the different histological types of lung cancer, with particular respect to CTC subtypes, cut-offs and time points of CTC enumeration.
We searched MEDLINE, Web of Science and Embase alongside relevant studies evaluating the prognostic value of CTCs in lung cancer patients. A random-effects model was used for meta-analysis, calculating hazard ratios (HRs), 95% confidence intervals and p-values.
27 studies enrolling 2957 patients were included. CTC detection indicates poor prognosis, especially in small cell lung cancer (SCLC) patients (overall survival HR 3.11, 95% CI 2.59-3.73) and predicts a worse outcome compared to nonsmall cell lung cancer patients. Epithelial CTCs predict a worse outcome for lung cancer than mesenchymal CTCs or epithelial-mesenchymal hybrids.
CTCs indicate poor prognosis in patients with primary lung cancer, with CTCs in SCLC having a more pronounced prognostic effect. The prognostic value of CTCs detected by different markers varies; most evidence is available for the strong negative prognostic effect of epithelial CTCs.
Circulating tumour cells (CTCs) serve as valuable biomarkers. However, EpCAM positive CTCs are less frequently detected in NSCLC patients compared to other epithelial tumours. First, EpCAM protein ...expression was analysed in primary and metastatic lung cancer tissue. In both groups 21% of the samples were EpCAM negative. Second, the CellSearch system identified 15% of patients (n = 48) as CTC positive whereas a multiplex RT-PCR for PIK3CA, AKT2, TWIST, and ALDH1 following EGFR, HER2 and EpCAM based enrichment detected CTCs in 29% of the patients. Interestingly, 86% of CTC positive patients were found to express ALDH1. Only 11% of the patients were CTC-positive by both techniques. CTC positivity was associated with patient disease state when assessed by the multiplex RT-PCR assay (p = 0.015). Patients harbouring tumours with an altered EGFR genotype were more frequently CTC-positive compared to patients with EGFR wildtype tumours. In subsets of patients, CTCs were found to express genes involved in resistance to therapy such as HER3 and MET. In conclusion, using multiple targets for CTC capture and identification increases the sensitivity of CTC detection in NSCLC patients, which can be explained by the presence of different CTC subtypes with distinct molecular features.
Lung cancer remains the leading cause of cancer-associated mortality worldwide, but with the emergence of oncogene targeted therapies, treatment options have tremendously improved. Owing to their ...biological relevance, members of the ERBB receptor family, including the EGF receptor (EGFR), HER2, HER3 and HER4, are among the best studied oncogenic drivers. Activating EGFR mutations are frequently observed in non-small cell lung cancer (NSCLC), and small molecule tyrosine kinase inhibitors (TKIs) are the established first line treatment option for patients whose tumors bear "typical/classical" EGFR mutations (exon 19 deletions, L858R point mutations). Additionally, new TKIs are rapidly evolving with better efficacy to overcome primary and secondary treatment resistance (e.g., that due to T790M or C797S resistance mutations). Some atypical EGFR mutations, such as the most frequent exon 20 insertions, exhibit relative resistance to earlier generation TKIs through steric hindrance. In this subgroup, newer TKIs, such as mobocertinib and the bi-specific antibody amivantamab have recently been approved, whereas less frequent atypical EGFR mutations remain understudied. In contrast to EGFR, HER2 has long remained a challenging target, but better structural understanding has led to the development of newer generations of TKIs. The recent FDA approval of the antibody-drug conjugate trastuzumab-deruxtecan for pretreated patients with HER2 mutant NSCLC has been an important therapeutic breakthrough. HER3 and HER4 also exert oncogenic potential, and targeted treatment approaches are being developed, particularly for HER3. Overall, strategies to inhibit the oncogenic function of ERBB receptors in NSCLC are currently evolving at an unprecedented pace; therefore, this review summarizes current treatment standards and discusses the outlook for future developments.
The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in ...osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect. Consequently, pharmacologic MERTK blockade by the small molecule inhibitor R992 increases osteoblast numbers and bone formation in mice. Furthermore, R992 counteracts cancer-induced bone loss, reduces bone metastasis and prolongs survival in preclinical models of multiple myeloma, breast- and lung cancer. In summary, MERTK and TYRO3 represent potent regulators of bone homeostasis with cell-type specific functions and MERTK blockade represents an osteoanabolic therapy with implications in cancer and beyond.
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