Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action

Tilsed, Caitlin M.; Fisher, Scott; Nowak, Anna K.; Lake, Richard; Lesterhuis, W. Joost

doi:10.3389/fonc.2022.960317

Cited by 57 publications

(36 citation statements)

References 208 publications

(105 reference statements)

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“…Starting the study of tumor oxygen state in the course of chemotherapy, we proceeded to that the effects of chemotherapy on tumors are due to both direct death of tumor cells and the delicate interplay between tumor vasculature responses and the inextricably linked changes in oxygen state [see Additional file 2 ] as well as its contribution to the processes driving the tumor cells death [ 46 , 47 ] . Accordingly, for the development of criteria predicting the sensitivity of breast tumors to chemotherapy, we used complementary methods: assessment of the dynamics of tumor volume and blood flow using US and the dynamics of tumor oxygenation by DOSI.…”

Section: Resultsmentioning

confidence: 99%

Changes in the tumor oxygenation but not in the tumor volume and tumor vascularization reflect early response of breast cancer to neoadjuvant chemotherapy

et al. 2023

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Background Breast cancer neoadjuvant chemotherapy (NACT) allows for assessing tumor sensitivity to systemic treatment, planning adjuvant treatment and follow-up. However, a sufficiently large number of patients fail to achieve the desired level of pathological tumor response while optimal early response assessment methods have not been established now. In our study, we simultaneously assessed the early chemotherapy-induced changes in the tumor volume by ultrasound (US), the tumor oxygenation by diffuse optical spectroscopy imaging (DOSI), and the state of the tumor vascular bed by Doppler US to elaborate the predictive criteria of breast tumor response to treatment. Methods A total of 133 patients with a confirmed diagnosis of invasive breast cancer stage II to III admitted to NACT following definitive breast surgery were enrolled, of those 103 were included in the final analysis. Tumor oxygenation by DOSI, tumor volume by US, and tumor vascularization by Doppler US were determined before the first and second cycle of NACT. After NACT completion, patients underwent surgery followed by pathological examination and assessment of the pathological tumor response. On the basis of these, data regression predictive models were created. Results We observed changes in all three parameters 3 weeks after the start of the treatment. However, a high predictive potential for early assessment of tumor sensitivity to NACT demonstrated only the level of oxygenation, ΔStO2, (ρ = 0.802, p ≤ 0.01). The regression model predicts the tumor response with a high probability of a correct conclusion (89.3%). The “Tumor volume” model and the “Vascularization index” model did not accurately predict the absence of a pathological tumor response to treatment (60.9% and 58.7%, respectively), while predicting a positive response to treatment was relatively better (78.9% and 75.4%, respectively). Conclusions Diffuse optical spectroscopy imaging appeared to be a robust tool for early predicting breast cancer response to chemotherapy. It may help identify patients who need additional molecular genetic study of the tumor in order to find the source of resistance to treatment, as well as to correct the treatment regimen.

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Section: Resultsmentioning

confidence: 99%

Changes in the tumor oxygenation but not in the tumor volume and tumor vascularization reflect early response of breast cancer to neoadjuvant chemotherapy

et al. 2023

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“…Chemotherapy mainly kills cancer cells and delays tumor growth by blocking the cell cycle, inhibiting DNA replication, interfering with cell metabolism, or inhibiting microtubule assembly. After cancer cell death, tumor antigens are presented by antigen-presenting cells, which leads to subsequent T cell recruitment, promotes the activation of the immune system, and thus promotes a highly effective antitumor immune response [ 8 , 164 , 165 ]. Induction of immunogenic cell death (ICD) is a critical way chemotherapy drugs work and can be induced by some anticancer drugs such as oxaliplatin.…”

Section: Effect Of Pd-1/pd-l1 Inhibitor Therapy Combining With Target...mentioning

confidence: 99%

Roles of tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for solid cancers

et al. 2023

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In recent years, tumor immunotherapy has made significant progress. However, tumor immunotherapy, particularly immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors), benefits only a tiny proportion of patients in solid cancers. The tumor microenvironment (TME) acts a significant role in tumor immunotherapy. Studies reported that tumor-associated macrophages (TAMs), as one of the main components of TME, seriously affected the therapeutic effect of PD-1/PD-L1 inhibitors. In this review, we analyzed TAMs from epigenetic and single-cell perspectives and introduced the role and mechanisms of TAMs in anti-programmed death protein 1(anti-PD-1) therapy. In addition, we summarized combination regimens that enhance the efficacy of tumor PD-1/PD-L1 inhibitors and elaborated on the role of the TAMs in different solid cancers. Eventually, the clinical value of TAMs by influencing the therapeutic effect of tumor PD-1/PD-L1 inhibitors was discussed. These above are beneficial to elucidate poor therapeutic effect of PD-1/PD-L1 inhibitors in solid tumors from the point of view of TAMs and explore the strategies to improve its objective remission rate of solid cancers.

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“…Consistent with these observations, we found marked ALPP upregulation in cancer cells that were subjected to growth-inhibitory stimuli including serum restriction, cell-cell contact inhibition, or treated with anti-proliferative chemotherapeutic 5-fluorouracil or gemcitabine or EGFR-targeting tyrosine kinase inhibitors. Of importance, enhancement of ALPP expression in cancer cells was transient and reversible, suggesting that ALPP is may be associated with cell quiescence [32,38,39,40,41,42,43,44].…”

Section: Discussionmentioning

confidence: 99%

EGFR inhibition in lung adenocarcinoma upregulates cell surface expression of the placental antigen ALPP and enhances efficacy of ALPP-ADC therapy

Chen

Hong

et al. 2023

Preprint

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Alkaline phosphatase placental type (ALPP) and ALPPL2 are closely related and regulated GPI anchored proteins that are known to be expressed on the cell surface in some cancers, whereas normal tissue expression is largely limited to the placenta. Clinical utility of ALPP is potentially limited by heterogenous expression in tumors. Here, we assessed ALPP and ALPPL2 surfaceome protein levels in 158 cancer cell lines and mRNA expression levels in 10,967 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), which revealed ALPP, and to a lesser extent ALPPL2, to be variably expressed in several cancer types including lung adenocarcinoma (LUAD). Surface expression of ALPP was confirmed by tissue microarray analysis of 204 lung tumors. Using LUAD as a model system, we demonstrated that treatment with EGFR inhibitors, or induction of cancer cell quiescence via nutrient deprivation greatly enhanced ALPP surface expression. Mechanistic studies revealed that enhancement of surface ALPP expression in LUAD following gefitinib treatment was mediated through repression of EGFR signaling and activation of the transcription factor FoxO3a, which was identified as an upstream transcriptional regulator of ALPP. Using xenograft models of LUAD, we further demonstrated that gefitinib treatment upregulates surface expression of ALPP in LUAD cells but not in normal tissues. Combination therapy with gefitinib and an ALPP antibody conjugated with Monomethylauristatin F (ALPP-ADC-MAF) resulted in superior anti-cancer efficacy compared with gefitinib or ALPP-ADC-MAF alone. Our findings support a novel combination treatment modality that boosts the efficacy of ALPP-ADC directed therapy.

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Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action

Cited by 57 publications

References 208 publications

Changes in the tumor oxygenation but not in the tumor volume and tumor vascularization reflect early response of breast cancer to neoadjuvant chemotherapy

Changes in the tumor oxygenation but not in the tumor volume and tumor vascularization reflect early response of breast cancer to neoadjuvant chemotherapy

Roles of tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for solid cancers

EGFR inhibition in lung adenocarcinoma upregulates cell surface expression of the placental antigen ALPP and enhances efficacy of ALPP-ADC therapy

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