Pulmonary Metastasis Of Breast Cancer Research Articles

Abstract 729: IDO1 inhibition enables IFNγ-elicited responsiveness of pulmonary breast cancer metastases to hypoxia-directed tumoricidal agents

Abstract In mouse models of lung carcinoma and pulmonary breast cancer metastasis, genetic ablation of the tryptophan catabolizing enzyme IDO1 (indoleamine 2,3-dioxygenase 1) resulted in restricted tumor outgrowth associated with attenuated induction of the inflammatory cytokine IL6 (interleukin 6). Utilizing the 4T1 breast cancer metastasis model to further elucidate the mechanistic basis underlying IDO1’s pro-tumor activity in the lungs established that IDO1 acts as an integral determinant of a tumor-promoting inflammatory state that supports neovascular retention. Ido1−/− (nullizygous) mice exhibited impaired pulmonary metastases neovascularization and outgrowth that was driven by IFNγ (interferon gamma) in the absence of IDO1-dependent IL6 production. Hypoxia was likewise elevated, and these stress conditions increased the susceptibility of the metastatic tumor cells to cytotoxicity associated with administration of GSK2656157, an inhibitor of PERK (protein kinase RNA-like ER kinase), which acts as a primary sensor for activating the UPR (unfolded protein response) survival pathway. In WT (wild type) mice with established 4T1 lung metastases, administration of the IDO1 inhibitors epacadostat, navoximod or indoximod each similarly resulted in rapid collapse of the metastatic tumor neovasculature and concomitantly increased intratumoral hypoxia and sensitivity to PERK inhibition. Therefore, while IDO1 inhibition does not directly promote effective tumor cell killing in this context, the disruption of blood supply due to IFNγ-mediated neovascular regression subjects the tumor cells to hypoxic environmental stress, raising the possibility for therapeutic intervention with selectively targeted agents. Combining chemotherapy with immune checkpoint blockade (ICB) is recognized as an effective strategy for treating lung cancer, with first-line therapy for some patients including the alkylating agent carboplatin in conjunction with pembrolizumab. The challenge remains, however, that chemotherapy causes systemic side effects that can negatively impact quality of life and limit efficacy. Evofosfamide is an alkylating prodrug that was designed to be selectively activated in regions of hypoxia, thereby limiting systemic exposure. We report that enhanced metastatic tumor cell killing with evofosfamide can be achieved by co-administration of an IDO1 inhibitor. Elevated intratumoral hypoxia has also previously been linked to increased expression levels of PDL1, a favorable indicator of ICB responsiveness, and we have confirmed the upregulation of PDL1 in 4T1 lung metastases following IDO1 inhibitor administration. Our data in the lung metastasis model support future studies to evaluate whether IDO1 inhibition can be effectively combined with evofosfamide and anti-PD1 treatment to improve therapeutic outcomes. Citation Format: Shih-Chun Shen, Souvik Dey, James B. DuHadaway, Erika Sutanto-Ward, George C. Prendergast, Alexander J. Muller. IDO1 inhibition enables IFNγ-elicited responsiveness of pulmonary breast cancer metastases to hypoxia-directed tumoricidal agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 729.

A Stable Open-Shell Conjugated Diradical Polymer with Ultra-High Photothermal Conversion Efficiency for NIR-II Photo-Immunotherapy of Metastatic Tumor

HighlightsBy employing side-chain regulation, the photothermal therapy response of conjugated diradical polymer can red-shift from near-infrared (NIR)-I to the NIR-II region. This strategy offers new radical materials in developing NIR-II photothermal materials.The conjugated diradical polymer TTB-2 receives a record-high photothermal conversion efficiency of 87.7%, far beyond the recently reported NIR-II photothermal agents. Such conjugated diradical polymer must enrich the NIR-II photothermal agents’ library and provide important insight for more diradical polymer construction.The conjugated diradical polymer nanoparticles TTB-2 NPs achieve good tumor photoablation with navigation of photoacoustic imaging in the NIR-II window, without any side effect. Furthermore, the efficient photo-immunity effect prevents the pulmonary metastasis of breast cancer.

Stanniocalcin 1 promotes lung metastasis of breast cancer by enhancing EGFR–ERK–S100A4 signaling

Lung metastasis is the leading cause of breast cancer-related death. The tumor microenvironment contributes to the metastatic colonization of tumor cells in the lungs. Tumor secretory factors are important mediators for the adaptation of cancer cells to foreign microenvironments. Here, we report that tumor-secreted stanniocalcin 1 (STC1) promotes the pulmonary metastasis of breast cancer by enhancing the invasiveness of tumor cells and promoting angiogenesis and lung fibroblast activation in the metastatic microenvironment. The results show that STC1 modifies the metastatic microenvironment through its autocrine action on breast cancer cells. Specifically, STC1 upregulates the expression of S100 calcium-binding protein A4 (S100A4) by facilitating the phosphorylation of EGFR and ERK signaling in breast cancer cells. S100A4 mediates the effect of STC1 on angiogenesis and lung fibroblasts. Importantly, S100A4 knockdown diminishes STC1-induced lung metastasis of breast cancer. Moreover, activated JNK signaling upregulates STC1 expression in breast cancer cells with lung-tropism. Overall, our findings reveal that STC1 plays important role in breast cancer lung metastasis.

Mucosal vaccination with an adenoviral vector vaccine protects against pulmonary breast cancer metastasis by robust induction of tissue-resident memory T-cells in the lung

Abstract The presence of tissue-resident memory T-cells (TRM) in solid tumors positively correlates with an improved overall prognosis and responsiveness to checkpoint inhibitor therapy. Rationally designed vaccine approaches capable of inducing antitumor TRM at cancer sites are needed to harness the full potential of localized immunity in tumor therapy. Our project aims to establish tumor antigen-specific lung TRM by mucosal vaccination with an adenoviral (Ad) vaccine to prevent and treat lung metastasis in the murine 4T1 breast cancer model. We employ Ad serotype 5 vectors encoding for 4T1 tumor-associated antigens from Mage-b and MuLV gp70 for intranasal vaccination, supplemented with an Interleukin-1β-encoding vector to specifically boost lung TRM induction. Indeed, particularly if Ad-IL-1β was co-delivered, mucosal vaccination established high numbers of tumor antigen-specific CD69 +CD103 +lung TRM as shown by phenotypic and functional analyses in combination with intravascular staining. Vaccine efficacy was evaluated in a 4T1 pseudometastasis model mimicking a prophylactic vaccination against lung metastasis in breast cancer patients. Local immunization led to a significant protection against pulmonary metastasis and improved survival compared to non-vaccinated and, notably, intramuscularly immunized mice. By using FTY720 to inhibit T-cell circulation upon tumor challenge, we confirmed that TRM are crucial contributors to the vaccine efficacy. In conclusion, induction of tumor-antigen specific lung TRM are a key point in local protection against pulmonary metastasis. Ongoing studies analyze the therapeutic use of this vaccination strategy as well as its potential in combination with immune checkpoint inhibition. Supported by grants from 'Anschubfinanzierung (ELAN) im IZKF' and 'Doktor Robert Pfleger-Stiftung'.

Photothermal “nano-dot” reactivate “immune-hot” for tumor treatment via reprogramming cancer cells metabolism

Cancer immunotherapy, despite its enormous application prospect, is trapped in the abnormal lactic acid metabolism of tumor cells that usually causes an immunosuppressive tumor microenvironment (ITM). Inducing immunogenic cell death (ICD) not only sensitizes cancer cells to carcer immunity, but also leads to a great increase in tumor-specific antigens. It improves tumor condition from “immune-cold” to “immune-hot”. Herein, a near-infrared photothermal agent NR840 was developed and encapsulated into tumor-targeted polymer DSPE-PEG-cRGD and carried lactate oxidase (LOX) by electrostatic interaction, forming self-assembling “nano-dot” PLNR840 with high loading capacity for synergistic antitumor photo-immunotherapy. In this strategy, PLNR840 was swallowed by cancer cells, then dye NR840 was excited at 808 nm to generate heat inducing tumor cell necrosis, which further caused ICD. LOX could serve as a catalyst, reducing lactic acid efflux via regulation of cell metabolism. More importantly, the consumption of intratumoral lactic acid could substantially reverse ITM, including promoting the polarization of tumor-associated macrophages from M2 to M1 type, inhibiting the viability of regulatory T cells for sensitizing photothermal therapy (PTT). After the combination of αPD-L1 (programmed cell death protein ligand 1), PLNR840 restored CD8+ T-cell activity that thoroughly cleaned the pulmonary metastasis of breast cancer in 4T1 mouse model and cured hepatocellular carcinoma in Hepa1-6 mouse model. This study provided an effective PTT strategy to boost “immune-hot” and reprogrammed tumor metabolism for antitumor immunotherapy.

Platycodin D induces neutrophil apoptosis by downregulating PD-L1 expression to inhibit breast cancer pulmonary metastasis.

During breast cancer development, programmed cell death 1 ligand 1 (PD-L1) overexpression in neutrophils leads to delayed apoptosis and promotes neutrophil hyperproliferation in the lung to form a premetastatic niche, which is beneficial for pulmonary metastasis. Platycodin D (PlaD), a triterpenoid saponin with known anti-inflammatory and antitumor effects, has been reported to downregulate PD-L1 expression. This study aimed to investigate the inhibitory effect of PlaD on neutrophil PD-L1 in 4T1 tumor-bearing mice and the potential mechanism of breast cancer pulmonary metastasis. In this study, the orthotopic 4T1 murine mammary carcinoma model was administered 10 and 20mg/kg PlaD by gavage. PlaD reduced the excess neutrophils and decreased their high migratory capacity in bone marrow, peripheral blood and lung tissue in the premetastatic period, thereby effectively inhibiting tumor growth and pulmonary metastasis. Moreover, PlaD inhibited the phosphatidylinositol-3-kinase (PI3K)/Akt pathway by decreasing the expression of PD-L1 in neutrophils and promoted neutrophil apoptosis. In vitro, PlaD treatment decreased the viability and inhibited migration of neutrophil-like dHL-60 in a dose-dependent manner. Similarly, PlaD inhibited the increase in PD-L1 induced by IFN-γ stimulation and subsequently induced apoptosis in dHL-60 cells. In conclusion, the administration of PlaD inhibited the PI3K/Akt signaling pathway by reducing the expression of PD-L1 in neutrophils. PlaD promoted neutrophil apoptosis, thereby inhibiting the establishment of a premetastatic niche and ultimately blocking the development of pulmonary metastasis.

Stealth-like polysarcosine-modified nanoparticles with low dye doses and long blood circulation for efficient breast cancer pulmonary metastasis imaging.

Fluorescence imaging (FLI) in the near-infrared-II (NIR-II; 1000-1700 nm) window holds great potential for cancer metastasis imaging owing to its deep tissue penetration and a high signal-to-background ratio. However, currently reported organic NIR-II contrast agents generally present problems such as poor water solubility, low NIR-II fluorescence quantum yield (QY), short blood circulation half-life (t1/2), high injection doses, and undesirable tumor accumulation. In this study, an NIR-II small-molecule-based polymer (TQF-PSar) modified with four dense/hydrophilic polysarcosine (PSar) arms was prepared for efficient breast cancer pulmonary metastasis imaging. The NIR-II intensity of TQF-PSar (whose QY was calculated to be 1%) was 26.4-fold higher than that of the PEGylated nanoparticles (TQF-PEG NPs) at the same low dye dose (core TQF concentration: 2.5 μg mL-1). Moreover, owing to the ideal stealth character, TQF-PSar displayed a more prolonged blood circulation t1/2 (36.9 h) and better tumor accumulation capability than TQF-PEG NPs even at this low dye concentration. Finally, the successful use of TQF-PSar in noninvasive NIR-II FLI for breast cancer pulmonary metastasis was demonstrated in living mice.

Micellar nanoparticles inhibit the postoperative inflammation, recurrence and pulmonary metastasis of 4T1 breast cancer by blocking NF-κB pathway and promoting MDSCs depletion

The progression of breast cancer can stimulate the production of myeloid-derived suppressor cells (MDSCs). These cells with significant immunosuppressive activity play a key role in promoting the formation of pulmonary inflammatory and immunosuppressive microenvironment, namely pre-metastatic niche (PMN). Surgical resection of tumors often leads to strong inflammatory reactions, and the produced circulating tumor cells (CTCs) can implant into PMN to promote the recurrence and pulmonary metastasis of breast cancer. Therefore, we developed a hyaluronic acid (HA)-coated chitosan oligosaccharide-all-trans-retinoic-acid (COS-ATRA) micellar nanoparticle loaded with chemotherapeutic drug doxorubicin (DOX) (HA@CA/DOX NPs). The hydrophilic segment COS and hydrophobic segment ATRA both blocked NF-κB inflammatory signaling pathway in 4T1 tumor cells and MDSCs and alleviated the inflammation after resection. Besides, ATRA also significantly depleted MDSCs in lungs and tumors, thereby regulating the inflammatory and immunosuppressive microenvironment and inhibiting the formation of PMN. HA coated on the surface of nanoparticles shielded the excessive positive charge and achieved tumor targeting through CD44 on the surface of tumor cells. This drug delivery system combined with anti-inflammation and chemotherapy significantly inhibited the postoperative recurrence and pulmonary metastasis of breast cancer.

Resveratrol reverses TGF-β1-mediated invasion and metastasis of breast cancer cells via the SIRT3/AMPK/autophagy signal axis.

Resveratrol (Resv) has antitumorigenic and antimetastatic activities; however, the molecular mechanisms underlying the inhibitory effects of Resv on the invasion and metastasis of breast cancer cells are still a subject of debate. In our study, we demonstrated that Resv inhibited tumor cell proliferation and tumor growth. It also suppressed invasion and pulmonary metastasis of breast cancer by reversing the transforming growth factor beta 1 (TGF-β1)-mediated EMT process. Meanwhile, the anticarcinogenic effects of Resv were abolished by the autophagy blocker 3-methyladenine (3-MA) or Beclin 1 small interfering RNA. Moreover, Resv upregulated autophagy-related genes and protein levels and induced the formation of autophagosomes in 4T1 breast cancer cells and xenograft mice, suggesting that autophagy was involved in the anticarcinogenic activities of Resv in both models. In addition, Resv-induced autophagy by increasing the expression of SIRT3 and phosphorylated AMPK. SIRT3 knockdown reduced AMPK phosphorylation and autophagy-related proteins levels, and suppressed the anticancer effects of Resv, demonstrating that the inhibitory effects of Resv on tumor progression were mediated via the SIRT3/AMPK/autophagy pathway. Taken together, our study provided novel insight into the anticancer effects of Resv and revealed that targeting the SIRT3/AMPK/autophagy pathway can serve as a new therapeutic target against breast cancer.

Red-light-triggered self-destructive mesoporous silica nanoparticles for cascade-amplifying chemo-photodynamic therapy favoring antitumor immune responses

Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effects in malignant tumors, the light-controlled drug release, synergism and biocompatibility of current nanocarriers are limited. Herein, we report a red light-responsive, self-destructive carrier constructed using polyethylene glycol-modified, diselenide-bridged mesoporous silica nanoparticles. The carrier is co-encapsulated with the chemo-drug doxorubicin and the photosensitizer methylene blue for chemo-photodynamic therapy. Upon low-dose red light irradiation during photodynamic therapy (PDT), the reactive oxygen species (ROS) mediates a diselenide bond cleavage resulting in the degradation of the organosilica matrix and a dual drug release. This, in turn, results in a synergistic chemo-photodynamic performance in vitro and in vivo. More importantly, such cascade chemo-PDT boosts immunogenic cell death and robust anti-tumor immunity responses. Combination with a PD-1 checkpoint blockade further evokes a series of systemic immunity responses that suppress distant tumor growth and the pulmonary metastasis of breast cancer, as well as offer long-term protection against recurrent tumors. The presented work offers a controllable self-destruction nanoplatform for cascade-amplifying chemo-photodynamic therapy in response to external red light radiation.

A light-driven dual-nanotransformer with deep tumor penetration for efficient chemo-immunotherapy.

Designing a transformable nanosystem with improved tumor accumulation and penetration by tuning multiple physicochemical properties remains a challenge. Here, a near-infrared (NIR) light-driven nanosystem with size and charge dual-transformation for deep tumor penetration is developed.Methods: The core-shell nanotransformer is realized by integrating diselenide-bridged mesoporous organosilica nanoparticles as a reactive oxygen species (ROS)-responsive core with an indocyanine green (ICG)-hybrid N-isopropyl acrylamide layer as a thermosensitive shell. After loading doxorubicin (DOX), negatively charged nanomedicine prevents DOX leakage, rendering prolonged blood circulation time and high tumor accumulation.Results: Upon NIR light irradiation, mild photothermal effects facilitate the dissociation of the thermosensitive shell to achieve negative-to-positive charge reversal. Meanwhile, ICG-generated ROS cleave the diselenide bond of the organosilica core, resulting in rapid matrix degradation that produces DOX-containing smaller fragments. Such a light-driven dual-transformable nanomedicine simultaneously promotes deep tumor penetration and implements sufficient chemotherapy, along with evoking robust immunogenic cell death effects in vitro and in vivo. With the combination of a programmed cell death protein-1 (PD-1) checkpoint blockade, the nanotransformer remarkably blocks primary tumor growth and pulmonary metastasis of breast cancer with low systemic toxicity.Conclusions: This study develops a promising strategy to realize high tumor accumulation and deep penetration of light-transformable nanomedicine for efficient and safe chemo-immunotherapy.

Chemoimmunotherapy: Coordination and Redox Dual‐Responsive Mesoporous Organosilica Nanoparticles Amplify Immunogenic Cell Death for Cancer Chemoimmunotherapy (Small 26/2021)

In article number 2100006, Wen Sun, Wen-fei Dong, Dan Shao, and co-workers fabricate diselenide-bridged mesoporous organosilica nanoparticles for coordination and redox dual-responsive delivery of chemotherapeutic ruthenium compound KP1339. Such immunogenic cell death nano-amplifier performed robust suppression on primary and distant tumor growth, as well as pulmonary metastasis of breast cancer with low systematic toxicity when combined with anti-PD-L1.

Coordination and Redox Dual-Responsive Mesoporous Organosilica Nanoparticles Amplify Immunogenic Cell Death for Cancer Chemoimmunotherapy.

Amplifying the chemotherapy-driven immunogenic cell death (ICD) for efficient and safe cancer chemoimmunotherapy remains a challenge. Here, a potential ICD nanoamplifier containing diselenide-bridged mesoporous organosilica nanoparticles (MONs) and chemotherapeutic ruthenium compound (KP1339) to achieve cancer chemoimmunotherapy is tailored. KP1339-loaded MONs show controlled drug release profiles via glutathione (GSH)-responsive competitive coordination and matrix degradation. High concentration of MONs selectively evoked reactive oxygen species production, GSH depletion, and endoplasmic reticulum stress in cancer cells, thus amplifying the ICD of KP1339 and boosting robust antitumor immunological responses. After the combination of PD-L1 checkpoint blockade, cancer cell membrane-cloaked KP1339-loaded MONs not only regress primary tumor growth with low systemic toxicity, but also inhibit distant tumor growth and pulmonary metastasis of breast cancer. The results have shown the potential of coordination and redox dual-responsive MONs boosting amplified ICD for cancer chemoimmunotherapy.

Eosinophils inhibit breast cancer pulmonary metastatic colonization and directly kill tumor cells via degranulation

Abstract Metastatic breast cancer remains incredibly challenging to treat, highlighting the need for an improved understanding of host factors that prevent metastasis, as well as improved therapeutics to treat metastatic cancer. The lungs, which are one of the most common sites of breast cancer metastasis, are host to a variety of immune cell subsets, including eosinophils (Eo), which are innate immune cells that target pathogens via the secretion of cytotoxic granule proteins. Eo have been shown to be anti-tumorigenic when exposed to certain signals from their local microenvironment. To study the role of eosinophils in pulmonary breast cancer metastasis, we utilized transgenic mouse models of eosinophilia (IL5Tg mice) and eosinophil-deficiency (ddGATA mice). EO771 breast cancer cells were injected intravenously (IV) to seed the lungs. We found that IL5Tg mice, which have a systemic expansion of Eo, had significantly lower EO771 lung tumor burden compared to WT mice. We found that Eo-deficient ddGATA mice exhibited accelerated metastatic progression compared to both WT and IL5Tg mice injected IV with EO771 cells. We also found that WT mice had an increased number of lung EO771 tumor cells compared to IL5Tg mice merely 5 days post-IV injection, indicating that Eo may play a role in both initial tumor cell seeding and subsequent metastatic nodule progression. Importantly, we found that Eo co-cultured with EO771 and LLC tumor cells released eosinophil peroxidase, a cytotoxic granule protein, resulting in tumor cell killing. These results highlight a role for Eo in preventing tumor cell colonization to metastatic sites and suggest that developing drugs to trigger Eo degranulation may serve as a viable therapeutic option to treat metastatic disease.

Abstract IA018: Linking obesity-associated inflammation with cancer metastasis

Abstract Obesity is associated with increased incidence and mortality of multiple tumor types, and competes with smoking tobacco as the leading preventable risk factor for all cancer-related deaths. In breast cancer, epidemiological studies have shown that obesity is linked to enhanced metastasis to lung and liver. However, it is not known how to improve cancer outcomes in the obese patient population as the mechanistic link between obesity and cancer progression is currently lacking. Using genetic and diet-induced obesity mouse models, it was previously shown that obesity promotes pulmonary metastasis of breast cancer by inducing lung neutrophilia via a IL5–GM-CSF signaling axis. We have now determined that neutrophils are reprogrammed by obesity within the lung to produce elevated levels of reactive oxygen species (ROS) and release neutrophil extracellular traps (NETs). This in turn weakens endothelial barrier integrity, leading to enhanced microvascular permeability and tumor cell extravasation into the lung parenchyma. This effect can be reversed by targeting ROS via pharmacological or genetic approaches, or by preventing NETosis using PAD4 inhibitors. To confirm the translational relevance of our findings, we performed imaging mass cytometry on lung metastasis samples from cancer patients, and observed a significant correlation between body mass index and NETosis, neutrophil oxidative burst, and ROS status. Given the high prevalence of obesity on an international scale, our data provide insight into mechanisms of cancer progression for a significant proportion of the adult population, including (potentially) those who are metabolically obese but normal weight. Citation Format: Sheri A. McDowell, Robin Luo, Jonathan D. Spicer, Andrew J. Dannenberg, Logan A. Walsh, Daniela F. Quail. Linking obesity-associated inflammation with cancer metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA018.

Targeting FAPα-expressing tumor-associated mesenchymal stromal cells inhibits triple-negative breast cancer pulmonary metastasis.

Tumor metastasis is the main cause of death in patients with triple-negative breast cancer (TNBC). Bone marrow-derived mesenchymal stem cells (BM-MSCs) have tropism towards tumor tissues, and can be converted into tumor-associated mesenchymal stromal cells (TA-MSCs) to facilitate TNBC metastasis through interactions with tumor-associated macrophages (TAMs). However, the underlying molecular mechanisms are complex and unclear, and effective strategies to suppress tumor metastasis via eliminating TA-MSCs are still lacking. Here, we demonstrate that fibroblast activation protein alpha (FAPα) was overexpressed in TA-MSCs, which prompts TA-MSCs to secrete multiple C-C motif chemokine ligands, promoting C-C motif chemokine receptor 2 (CCR2)+ TAM recruitment and facilitating TAM polarization into the M2 phenotype, thereby promoting TNBC pulmonary metastasis. Z-GP-DAVLBH, an FAPα-activated vinblastine prodrug, induces FAPα+ TA-MSC apoptosis, which significantly suppresses CCR2+ TAM recruitment and polarization, thus inhibiting pulmonary metastasis of orthotopic TNBC cell-derived xenografts and patient-derived xenografts. This study provides insight into an important role of FAPα in mediating TA-MSC-induced TNBC metastasis and provides compelling evidence that targeting TA-MSCs with an FAPα-activated prodrug is a promising strategy for suppressing TNBC metastasis.

Fourier Transform Infrared Polarization Contrast Imaging Recognizes Proteins Degradation in Lungs upon Metastasis from Breast Cancer.

Simple SummarySeveral lung extracellular matrix (ECM) proteins are involved in the formation of a metastatic niche in pulmonary metastasis and they accompany the cancer progression. Its gradual remodeling does not induce compositional changes of its components, but it is related to the re-distribution of individual proteins, their cross-linking and spatial arrangement within the tissue. The combination of FTIR and FTIR polarization contrast (PCI) imaging, as rapid, non-destructive, and label-free techniques, allows for the determination of protein alternations occurring in lungs that are affected by breast cancer metastasis. Both have the potential to characterize biochemical changes of the metastatic target, can determine phenotypes of tissue structures, and deliver a novel spectroscopic marker panel for the recognition of metastasis environment.The current understanding of mechanisms underlying the formation of metastatic tumors has required multi-parametric methods. The tissue micro-environment in secondary organs is not easily evaluated due to complex interpretation with existing tools. Here, we demonstrate the detection of structural modifications in proteins using emerging Fourier Transform Infrared (FTIR) imaging combined with light polarization. We investigated lungs affected by breast cancer metastasis in the orthotopic murine model from the pre-metastatic phase, through early micro-metastasis, up to an advanced phase, in which solid tumors are developed in lung parenchyma. The two IR-light polarization techniques revealed, for the first time, the orientational ordering of proteins upon the progression of pulmonary metastasis of breast cancer. Their distribution was complemented by detailed histological examination. Polarized contrast imaging recognised tissue structures of lungs and showed deformations in protein scaffolds induced by inflammatory infiltration, fibrosis, and tumor growth. This effect was recognised by not only changes in absorbance of the spectral bands but also by the band shifts and the appearance of new signals. Therefore, we proposed this approach as a useful tool for evaluation of progressive and irreversible molecular changes that occur sequentially in the metastatic process.

Pulmonary metastasectomy for pulmonary metastasis of breast cancer has a limited prognostic impact: a multi-institutional retrospective analysis.

BackgroundPulmonary metastasectomy (PM) for breast cancer-derived pulmonary metastasis is controversial. This study aimed to assess the prognostic factors and implication of PM for metastatic breast cancer using a multi-institutional database.MethodsClinical data of 253 females with pulmonary metastasis of breast cancer who underwent PM between 1982 and 2017 were analyzed retrospectively.ResultsThe median patient age was 56 years. The median follow-up period was 5.4 years, and the median disease-free interval (DFI) was 4.8 years. The 5- and 10-year survival rates after PM were 64.9% and 50.4%, respectively, and the median overall survival was 10.1 years. Univariate analysis revealed that the period of PM before 2000, a DFI <36 months, lobectomy/pneumonectomy, large tumor size, and lymph node metastasis were predictive of a worse overall survival. In the multivariate analysis, a DFI <36 months, large tumor size, and lymph node metastasis remained significantly related to overall survival. The 5- and 10-year cancer-specific survival rates after PM were 66.9% and 54.7%, respectively, and the median cancer-specific survival was 13.1 years. Univariate analyses revealed that the period of PM before 2000, DFI <36 months, lobectomy/pneumonectomy, large tumor size, lymph node metastasis, and incomplete resection were predictive of a worse cancer-specific survival. Multivariate analysis confirmed that a DFI <36 months, large tumor size and incomplete resection were significantly related to cancer-specific survival.ConclusionsAs PM has limited efficacy in breast cancer, it should be considered an optional treatment for pulmonary metastasis of breast cancer.

Surgical therapy for pulmonary metastasis of breast cancer.

Metastatic breast cancer (MBC) is a disease with heterogeneous manifestations that arise from a variety of modes of spread from the primary disease. The lung is a common site of metastasis from breast cancer. A solitary lung nodule appearing on radiological examination following breast cancer treatment is likely to be diagnosed as pulmonary metastasis from breast cancer. However, the reported final pathological diagnoses include primary lung cancer and MBC in approximately 48–67% and 23–43% of cases, respectively. Moreover, some pulmonary metastases of breast cancer have radiological and histological characteristics similar to those of primary lung cancer. Thus, the differential diagnosis of a solitary lung nodule after treatment of breast cancer is challenging. Oligometastatic disease (OMD) is characterized by solitary or limited numbers of detectable metastatic lesions. OMD in the lung from colorectal cancer can be considered for locoregional treatments either alone or in combination with systemic therapy. In MBC patients, the indication for locoregional treatments for pulmonary metastasis is controversial, whereas surgical intervention can be performed to obtain tissue for histological and molecular confirmation and occasionally for curative intent in selected MBC patients. While several retrospective studies have examined the clinical impact of pulmonary metastasectomy (PM) in MBC patients, no prospective randomized trials have been conducted. Our systematic review of PM in MBC patients found that PM might offer a survival advantage in selected MBC patients with a long disease-free interval (DFI), small number of pulmonary metastases, complete resection, and/or hormone receptor positivity. Metastases are usually detected by radiological examinations such as computed tomography (CT) and positron emission tomography-CT. The detectability of these radiological examinations mainly depends on tumor size (size-dependent manner). By contrast, the amount of circulating tumor DNA (ctDNA) released by apoptotic or necrotic tumor cells depends on the tumor burden in the whole body, regardless of radiological detectability (dose-dependent manner). Since ctDNA assays reportedly reveal residual disease several weeks earlier than radiologic imaging does, monitoring for radiological tumor size and ctDNA concentration during the clinical course may help to inform the indication for local treatment in patients with MBC and may improve their clinical outcomes. This article reviewed the current status of PM in MBC patients with pulmonary metastasis and discussed future perspectives.

Interleukin-33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development.

Increasing evidence suggests that IL-33 plays an important role in regulating tumor development. However, conflicting results, obtained from numerous studies, have highlighted the divergent functions of IL-33. The detailed mechanisms by which IL-33 modulates tumor development merit further investigation. Here, we report that IL-33 administration can effectively inhibit the development of pulmonary metastasis of breast cancer in a mouse. In our model, IL-33 promotes the production of TNF-α by macrophages, which increases IL-33 specific receptor (ST2) expression on natural killer (NK) cells and is pivotal in IL-33-induced NK cell activation. IL-33 treatment also facilitates the production of CCL5 in the lung by eosinophils and CD8+ T cells, which mediates the recruitment of NK cells to the tumor microenvironment. The systemic activation and local recruitment of NK cells result in potent tumor rejection in the lung. Our study reports a novel mechanism for the IL-33-meditated suppression of metastatic cancer and provides potential therapeutic strategies for targeting metastatic tumor.