Oral bacterium Streptococcus mutans promotes tumor metastasis through thrombosis formation.

Thrombosis is a well-known cardiovascular disease (CVD) complication that has caused death in many patients with cancer. Oral bacteria have been reported to contribute to systemic diseases, including CVDs, and tumor metastasis. However, whether oral bacteria-induced thrombosis induces tumor metastasis remains poorly understood. In this study, the cariogenic oral bacterium Streptococcus mutans was used to examine thrombosis in vitro and in vivo. Investigation of tumor metastasis to the lungs was undertaken by intravenous S. mutans implantation using a murine breast cancer metastasis model. The results indicated that platelet activation, aggregation, and coagulation were significantly altered in S. mutans-stimulated endothelial cells (ECs), with elevated neutrophil migration, thereby inducing thrombosis formation. Streptococcus mutans stimulation significantly enhances platelet and tumor cell adhesion to the inflamed ECs. Furthermore, S. mutans-induced pulmonary thrombosis promotes breast cancer cell metastasis to the lungs in vivo, which can be reduced by using aspirin, an antiplatelet drug. Our findings indicate that oral bacteria promote tumor metastasis through thrombosis formation. Oral health management is important to prevent CVDs, tumor metastasis, and their associated death.

Nationwide prospective registry database of patients with newly diagnosed untreated pleural mesothelioma in Japan.

Due to the scarcity of large-sized prospective databases, the Japanese Joint Committee for Lung Cancer Registry conducted a nationwide prospective registry for newly diagnosed and untreated pleural mesothelioma. All new cases diagnosed pathologically as any subtype of pleural mesothelioma in Japan during the period between April 1, 2017, to March 31, 2019, were included before treatment. Data on survival were collected in April 2021. The eligible 346 patients (285 men [82.3%]; 61 women [17.7%]; median age, 71.0 years [range, 44-88]) were included for analysis. Among these patients, 138 (39.9%) underwent surgery, 164 (47.4%) underwent non-surgical therapy, and the remaining 44 (12.7%) underwent best supportive care. The median overall survival for all 346 patients was 19.0 months. Survival rates at 1, 2, and 3 years for all patients were, 62.8%, 42.3%, and 26.5%, respectively. Median overall survival was significantly different among patients undergoing surgery, non-surgical treatment, and best supportive care (32.2 months vs. 14.0 months vs. 3.8 months, p < 0.001). The median overall survival of patients undergoing pleurectomy/decortication and extrapleural pneumonectomy was 41.8 months and 25.0 months, respectively. Macroscopic complete resection resulted in longer overall survival than R2 resection and partial pleurectomy/exploratory thoracotomy (41.8 months vs. 32.2 months vs. 16.8 months, p < 0.001). Tumor shape, maximum tumor thickness, and sum of three level thickness were significant prognostic factors. The data in the prospective database would serve as a valuable reference for clinical practice and further studies for pleural mesothelioma.

Low-dose metronomic cisplatin as an antiangiogenic and anti-inflammatory strategy for cancer.

BACKGROUND: Conventional chemotherapy is based on the maximum tolerated dose (MTD) and requires treatment-free intervals to restore normal host cells. MTD chemotherapy may induce angiogenesis or immunosuppressive cell infiltration during treatment-free intervals. Low-dose metronomic (LDM) chemotherapy is defined as frequent administration at lower doses and causes less inflammatory change, whereas MTD chemotherapy induces an inflammatory change. Although several LDM regimens have been applied, LDM cisplatin (CDDP) has been rarely reported. This study addressed the efficacy of LDM CDDP on tumour endothelial cell phenotypic alteration compared to MTD CDDP. METHODS: Tumour growth and metastasis were assessed in bladder cancer-bearing mice treated with LDM or MTD gemcitabine (GEM) and CDDP. To elucidate the therapeutic effects of LDM CDDP, the change of tumour vasculature, tumour-infiltrating immune cells and inflammatory changes were evaluated by histological analysis and mRNA expression in tumour tissues. RESULTS: Tumour growth and bone metastasis were more suppressed by LDM CDDP + MTD GEM treatment than MTD CDDP + MTD GEM. Myeloid-derived suppressor cell accumulation was reduced by LDM CDDP, whereas inflammatory change was induced in the tumour microenvironment by MTD CDDP. CONCLUSION: LDM CDDP does not cause inflammatory change unlike MTD CDDP, suggesting that it is a promising strategy in chemotherapy.

SlicerPIT: software development and implementation for planning and image-guided therapy in photoimmunotherapy.

BACKGROUND: Photoimmunotherapy is a treatment modality that induces targeted cell death by binding a molecular-targeted drug activated by infrared light to the tumor cells and subsequently illuminating the lesion with infrared light. For deep lesions, a needle catheter is used to puncture the tumor, and an illumination fiber (cylindrical diffuser) is inserted into the catheter lumen for internal illumination. However, it can be challenging to place the cylindrical diffusers in an appropriate position as the deep lesions cannot be often confirmed accurately during surgery. MATERIALS AND METHODS: We have developed "SlicerPIT", a planning simulation software for photoimmunotherapy. SlicerPIT allows users to place the cylindrical diffuser with its illumination range on preoperative images in 2D and 3D and export the planning data to external image-guided surgical navigation systems. We performed seven cycles of photoimmunotherapy with SlicerPIT in three patients with recurrent head and neck cancer. RESULTS: Preoperative planning for photoimmunotherapy was conducted using SlicerPIT, which could be imported into the navigation system. During the operation, we punctured the needle catheters along with the treatment plan on the navigation screen. Subsequently, intraoperative CT imaging was performed and overlaid with the preoperative treatment plan to confirm the alignment of the cylindrical diffusers as planned, followed by infrared light illumination. Postoperative imaging showed necrosis and shrinkage of the entire tumor in all cycles. CONCLUSION: SlicerPIT allows for detailed preoperative treatment planning and accurate puncture. It may be a valuable tool to improve the accuracy of photoimmunotherapy for deep lesions and improve patient outcomes.

Stroma biglycan expression can be a prognostic factor in prostate cancers.

OBJECTIVES: This study analyzes the relationship between biglycan expression in prostate cancer and clinicopathological parameters to clarify the potential link between biglycan and prognosis and progression to castration-resistant prostate cancer (CRPC). METHODS: We retrospectively analyzed 60 cases of prostate cancer patients who underwent robot-assisted laparoscopic radical prostatectomy in Hokkaido University Hospital. RESULTS: Biglycan was expressed in the tumor stroma but not in tumor cells. There was no significant relationship with biochemical recurrence (p = 0.5237), but the expression of biglycan was 36.1% in the group with progression to CRPC. This indicates a significant relationship with progression to CRPC (p = 0.0182). Furthermore, the expression of biglycan-positive blood vessels was significantly higher (15.9%) in the group with biochemical recurrence than in the group without biochemical recurrence (8.5%) (p = 0.0169). The biglycan-positive vessels were 28.6% in the group with progression to CRPC, which was significantly higher than that in the group without progression to CRPC (p < 0.0001). CONCLUSION: This is the first study to show that stroma biglycan is a useful prognostic factor for prostate cancer.

The oxidized-LDL/LOX-1 axis in tumor endothelial cells enhances metastasis by recruiting neutrophils and cancer cells.

Epidemiological relationships between cancer and cardiovascular diseases have been reported, but a molecular basis remains unclear. Some proteoglycans that strongly bind low-density-lipoprotein (LDL) are abundant both in atherosclerotic regions and in high metastatic-tumor tissue. LDL retention is crucial for the initiation of atherosclerosis, although its contribution to malignancy of cancer is not known. In our study, we show the importance of the accumulation of LDL in tumor metastasis. We demonstrated that high metastatic-tumor tissue contains high amounts of LDL and forms more oxidized LDL (ox-LDL). Interestingly, lectin-like ox-LDL receptor 1 (LOX-1), a receptor for ox-LDL and a recognized key molecule for cardiovascular diseases, was highly expressed in tumor endothelial cells (TECs). Neutrophils are important for ox-LDL formation. Since we observed the accumulation and activation of neutrophils in HM-tumors, we evaluated the involvement of LOX-1 in neutrophil migration and activation. LOX-1 induced neutrophil migration via CCL2 secretion from TECs, which was enhanced by ox-LDL. Finally, we show genetic manipulation of LOX-1 expression in TECs or tumor stroma tended to reduce lung metastasis. Thus, the LOX-1/ox-LDL axis in TECs may lead to the formation of a high metastatic-tumor microenvironment via attracting neutrophils.

The oral bacterium Streptococcus mutans promotes tumor metastasis by inducing vascular inflammation.

Recent studies have demonstrated a relationship between oral bacteria and systemic inflammation. Endothelial cells (ECs), which line blood vessels, control the opening and closing of the vascular barrier and contribute to hematogenous metastasis; however, the role of oral bacteria-induced vascular inflammation in tumor metastasis remains unclear. In this study, we examined the phenotypic changes in vascular ECs following Streptococcus mutans (S. mutans) stimulation in vitro and in vivo. The expression of molecules associated with vascular inflammation and barrier-associated adhesion was analyzed. Tumor metastasis was evaluated after intravenous injection of S. mutans in murine breast cancer hematogenous metastasis model. The results indicated that S. mutans invaded the ECs accompanied by inflammation and NF-κB activation. S. mutans exposure potentially disrupts endothelial integrity by decreasing vascular endothelial (VE)-cadherin expression. The migration and adhesion of tumor cells were enhanced in S. mutans-stimulated ECs. Furthermore, S. mutans-induced lung vascular inflammation promoted breast cancer cell metastasis to the lungs in vivo. The results indicate that oral bacteria promote tumor metastasis through vascular inflammation and the disruption of vascular barrier function. Improving oral hygiene in patients with cancer is of great significance in preventing postoperative pneumonia and tumor metastasis.

Novel antiangiogenic therapy targeting biglycan using tumor endothelial cell-specific liposomal siRNA delivery system.

Tumor blood vessels play important roles in tumor progression and metastasis. Targeting tumor endothelial cells (TECs) is one of the strategies for cancer therapy. We previously reported that biglycan, a small leucine-rich proteoglycan, is highly expressed in TECs. TECs utilize biglycan in an autocrine manner for migration and angiogenesis. Furthermore, TEC-derived biglycan stimulates tumor cell migration in a paracrine manner leading to tumor cell intravasation and metastasis. In this study, we explored the therapeutic effect of biglycan inhibition in the TECs of renal cell carcinoma using an in vivo siRNA delivery system known as a multifunctional envelope-type nanodevice (MEND), which contains a unique pH-sensitive cationic lipid. To specifically deliver MEND into TECs, we incorporated cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) into MEND because αV ß3 integrin, a receptor for cRGD, is selective and highly expressed in TECs. We developed RGD-MEND-encapsulating siRNA against biglycan. First, we confirmed that MEND was delivered into OS-RC-2 tumor-derived TECs and induced in vitro RNAi-mediated gene silencing. MEND was then injected intravenously into OS-RC-2 tumor-bearing mice. Flow cytometry analysis demonstrated that MEND was specifically delivered into TECs. Quantitative RT-PCR indicated that biglycan was knocked down by biglycan siRNA-containing MEND. Finally, we analyzed the therapeutic effect of biglycan silencing by MEND in TECs. Tumor growth was inhibited by biglycan siRNA-containing MEND. Tumor microenvironmental factors such as fibrosis were also normalized using biglycan inhibition in TECs. Biglycan in TECs can be a novel target for cancer treatment.

Effects of obesity on CC16 and their potential role in overweight/obese asthma.

INTRODUCTION: Club cell secretory protein-16 (CC16) is a major anti-inflammatory protein expressed in the airway; however, the potential role of CC16 on overweight/obese asthma has not been assessed. In this study, we examined whether obesity reduces airway/circulatory CC16 levels using experimental and epidemiological studies. Then, we explored the mediatory role of CC16 in the relationship of overweight/obesity with clinical asthma measures. METHODS: Circulating CC16 levels were assessed by ELISA in three independent human populations, including two groups of healthy and general populations and asthma patients. The percentage of cells expressing club markers in obese vs. non-obese mice and human airways was determined by immunohistochemistry. A causal mediation analysis was conducted to determine whether circulatory CC16 acted as a mediator between overweight/obesity and clinical asthma measures. RESULTS: BMI was significantly and monotonously associated with reduced circulating CC16 levels in all populations. The percentage of CC16-expressing cells was reduced in the small airways of both mice and humans with obesity. Finally, mediation analysis revealed significant contributions of circulatory CC16 in the association between BMI and clinical asthma measures; 21.8% of its total effect in BMI's association with airway hyperresponsiveness of healthy subjects (p = 0.09), 26.4% with asthma severity (p = 0.030), and 23% with the required dose of inhaled corticosteroid (p = 0.042). In logistic regression analysis, 1-SD decrease in serum CC16 levels of asthma patients was associated with 87% increased odds for high dose ICS requirement (p < 0.001). CONCLUSIONS: We demonstrate that airway/circulating CC16, which is inversely associated with BMI, may mediate development and severity in overweight/obese asthma.

Inhibition of stromal biglycan promotes normalization of the tumor microenvironment and enhances chemotherapeutic efficacy.

BACKGROUND: Biglycan is a proteoglycan found in the extracellular matrix. We have previously shown that biglycan is secreted from tumor endothelial cells and induces tumor angiogenesis and metastasis. However, the function of stroma biglycan in breast cancer is still unclear. METHODS: Biglycan gene analysis and its prognostic values in human breast cancers were based on TCGA data. E0771 breast cancer cells were injected into WT and Bgn KO mice, respectively. RESULTS: Breast cancer patients with high biglycan expression had worse distant metastasis-free survival. Furthermore, biglycan expression was higher in the tumor stromal compartment compared to the epithelial compartment. Knockout of biglycan in the stroma (Bgn KO) in E0771 tumor-bearing mice inhibited metastasis to the lung. Bgn KO also impaired tumor angiogenesis and normalized tumor vasculature by repressing tumor necrosis factor-ɑ/angiopoietin 2 signaling. Moreover, fibrosis was suppressed and CD8+ T cell infiltration was increased in tumor-bearing Bgn KO mice. Furthermore, chemotherapy drug delivery and efficacy were improved in vivo in Bgn KO mice. CONCLUSION: Our results suggest that targeting stromal biglycan may yield a potent and superior anticancer effect in breast cancer.

Correlation between endothelial CXCR7 expression and clinicopathological factors in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) impairs functionality and sensuousness resulting in poor quality of life. Biomarkers can predict disease trajectory and lead to effective treatments. Transcriptomics have identified genes that are upregulated in tumor endothelial cells (TECs) compared with normal endothelial cells (NECs). Among them, chemokine receptor 7 (CXCR7) is highly expressed in TECs of several cancers and involved in angiogenesis of TECs. However, levels of CXCR7 in OSCC blood vessels have not been fully investigated. In this study, we analyzed the correlation between CXCR7 expression in TECs and clinicopathological factors in OSCC. Immunohistochemistry for CXCR7 and CD34 was performed on 59 OSCC tissue specimens resected between 1996 and 2008 at Hokkaido University Hospital. CXCR7 expression in blood vessels was evaluated by the ratio of CXCR7+/CD34+ blood vessels. CXCR7 expression was 42% and 19% in tumor and non-tumor parts, respectively, suggesting that CXCR7 expression is higher in TECs than in NECs. CXCR7 expression in TECs correlated with advanced T-stage and cancer stage. Overall survival and disease-free survival rates were higher in low-expressing CXCR7 patients than in high-expressing. These results suggest that CXCR7 expression in blood vessels may be a useful diagnostic and prognostic marker for OSCC patients.

A novel approach for the complete extraction of large tumours in video-assisted thoracoscopic surgery.

BACKGROUND: Video-assisted thoracoscopic (VATS) lobectomy has recently become the standard for treating lung cancer. However, the complete removal of large tumours from the chest cavity is often difficult. Therefore, we developed a novel approach to extract large tumours from the wound without rib resection or fracture (the eXtraction of resected specimens through the Lower INterCostal route [XLINC] method). SUBJECTS AND METHODS: In XLINC, a skin incision is made on the tenth intercostal space, and the resected lung tissue is extracted. This retrospective study included patients who underwent VATS lobectomy using XLINC in our institution from 2016 to 2018. As a control group, six patients who had undergone thoracotomy during VATS surgery due to a large tumour diameter were included in the conversion group. RESULTS: Four men and six women (median age = 66 years, maximum median tumour diameter = 59 mm) were included in the study. The median length of the wound incision for XLINC was 4.5 (range: 4-8) cm. The median operative time was 183 min, and the estimated blood loss was 50 ml. Rib resection was not required, and no fractures were noted. The median length of hospital stay was 8 days. No patients developed major complications caused by XLINC. There were no significant differences, except in operation time and amount of blood loss, between the two groups. However, the XLINC group used fewer post-operative analgesics. CONCLUSION: Our report suggests that XLINC might be a simpler, less invasive procedure that could be used in patients with large tumours.

Left upper lobectomy is a risk factor for cerebral infarction after pulmonary resection: a multicentre, retrospective, case-control study in Japan.

PURPOSE: The anatomical site of resected lobes may influence postoperative cerebral infarction. The objective of the current study was to determine if left upper pulmonary lobectomy is a risk factor for postoperative cerebral infarction. METHODS: This was a retrospective case-control study in patients undergoing pulmonary lobectomy from 2004 to 2013 in Japan. We retrospectively identified 610 patients from 153 institutions who had developed postoperative cerebral infarction following pulmonary lobectomy. The control group consisted of 773 patients who underwent lobectomy without cerebral infarction during a randomly selected single month in 2009 at the same institutions. RESULTS: Factors associated with cerebral infarction were age [10-year intervals, odds ratio (OR): 1.46; 95% confidence interval (CI): 1.23-1.73; p < 0.001], male sex (OR 1.92; 95% CI 1.29-2.86; p = 0.001), presence of comorbidities (OR 1.82; 95% CI 1.35-2.44; p < 0.001), perioperative anti-platelet or anti-coagulant drug use (OR 1.71; 95% CI 1.20-2.45; p = 0.003), and lobectomy. Subgroup analyses revealed that cerebral infarction was strongly associated with left upper lobectomy. CONCLUSIONS: Our findings suggest that left upper lobectomy is associated with a higher risk of cerebral infarction than other types of lobectomy, particularly in the early postoperative period.

Correction to: Left upper lobectomy is a risk factor for cerebral infarction after pulmonary resection: a multicentre, retrospective, case-control study in Japan.

The original article can be found online.

Tumor Endothelial Cell-A Biological Tool for Translational Cancer Research.

Going from bench to bedside is a simplified description of translational research, with the ultimate goal being to improve the health status of mankind. Tumor endothelial cells (TECs) perform angiogenesis to support the growth, establishment, and dissemination of tumors to distant organs. TECs have various features that distinguish them from normal endothelial cells, which include alterations in gene expression patterns, higher angiogenic and metabolic activities, and drug resistance tendencies. The special characteristics of TECs enhance the vulnerability of tumor blood vessels toward antiangiogenic therapeutic strategies. Therefore, apart from being a viable therapeutic target, TECs would act as a better mediator between the bench (i.e., angiogenesis research) and the bedside (i.e., clinical application of drugs discovered through research). Exploitation of TEC characteristics could reveal unidentified strategies of enhancing and monitoring antiangiogenic therapy in the treatment of cancer, which are discussed in this review.

[Bronchial Stump Coverage Technique by da Vinci Xi].

da Vinci's greatest attractions are the fine images acquired with a high-resolution 3-dimensional( 3D) endoscope and the precise operation by forceps equipped with an articulated arm. We believed that complicated procedures can benefit from robot-assisted surgery. We have been actively performing collection and sewing of viable tissue using da Vinci Xi for the purpose of preventing bronchial stump fistulas. Of the 44 cases of lobectomy performed by the end of November 2019 using da Vinci Xi, 13 cases underwent bronchial stump covering. The covering procedure was intended for patients with conditions such as diabetes and a history of internal use of steroids. As the dressing, pedicled intercostal muscle was used in 4 cases, and free pericardial fat tissue was used in 9 cases. A good visual field was obtained by appropriately turning the oblique mirror upside down. The smoke emission effect of AirSeal was useful for securing the visual field. The dressing was sutured and fixed using 3-0 or 4-0 Prolene( SH) cut to a length of 10 to 12 cm. The postoperative course was good and bronchial stump fistula did not occur in all cases.

Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment.

BACKGROUND: Tumor endothelial cells (TECs) perform tumor angiogenesis, which is essential for tumor growth and metastasis. Tumor cells produce large amounts of lactic acid from glycolysis; however, the mechanism underlying the survival of TECs to enable tumor angiogenesis under high lactic acid conditions in tumors remains poorly understood. METHODOLOGY: The metabolomes of TECs and normal endothelial cells (NECs) were analyzed by capillary electrophoresis time-of-flight mass spectrometry. The expressions of pH regulators in TECs and NECs were determined by quantitative reverse transcription-PCR. Cell proliferation was measured by the MTS assay. Western blotting and ELISA were used to validate monocarboxylate transporter 1 and carbonic anhydrase 2 (CAII) protein expression within the cells, respectively. Human tumor xenograft models were used to access the effect of CA inhibition on tumor angiogenesis. Immunohistochemical staining was used to observe CAII expression, quantify tumor microvasculature, microvessel pericyte coverage, and hypoxia. RESULTS: The present study shows that, unlike NECs, TECs proliferate in lactic acidic. TECs showed an upregulated CAII expression both in vitro and in vivo. CAII knockdown decreased TEC survival under lactic acidosis and nutrient-replete conditions. Vascular endothelial growth factor A and vascular endothelial growth factor receptor signaling induced CAII expression in NECs. CAII inhibition with acetazolamide minimally reduced tumor angiogenesis in vivo. However, matured blood vessel number increased after acetazolamide treatment, similar to bevacizumab treatment. Additionally, acetazolamide-treated mice showed decreased lung metastasis. CONCLUSION: These findings suggest that due to their effect on blood vessel maturity, pH regulators like CAII are promising targets of antiangiogenic therapy. Video Abstract.

Development of Immortalized Human Tumor Endothelial Cells from Renal Cancer.

Tumor angiogenesis research and antiangiogenic drug development make use of cultured endothelial cells (ECs) including the human microvascular ECs among others. However, it has been reported that tumor ECs (TECs) are different from normal ECs (NECs). To functionally validate antiangiogenic drugs, cultured TECs are indispensable tools, but are not commercially available. Primary human TECs are available only in small quantities from surgical specimens and have a short life span in vitro due to their cellular senescence. We established immortalized human TECs (h-imTECs) and their normal counterparts (h-imNECs) by infection with lentivirus producing simian virus 40 large T antigen and human telomerase reverse transcriptase to overcome the replication barriers. These ECs exhibited an extended life span and retained their characteristic endothelial morphology, expression of endothelial marker, and ability of tube formation. Furthermore, h-imTECs showed their specific characteristics as TECs, such as increased proliferation and upregulation of TEC markers. Treatment with bevacizumab, an antiangiogenic drug, dramatically decreased h-imTEC survival, whereas the same treatment failed to alter immortalized NEC survival. Hence, these h-imTECs could be a valuable tool for drug screening to develop novel therapeutic agents specific to TECs or functional biological assays in tumor angiogenesis research.

Clinical Course of Histologically Proven Multifocal Micronodular Pneumocyte Hyperplasia in Tuberous Sclerosis Complex: A Case Series and Comparison with Lymphangiomyomatosis.

BACKGROUND: Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary manifestation of tuberous sclerosis complex (TSC). Because of its rarity, no previous study has described the detailed clinical course of this disease. OBJECTIVES: This study aimed to clarify the longitudinal clinical characteristics of subjects with MMPH. METHODS: Nine patients with MMPH diagnosed at Hokkaido University Hospital were retrospectively analyzed. Changes in computed tomography findings and pulmonary function were compared during the follow-up period. Serum levels of KL-6, surfactant protein (SP)-A, and SP-D were measured to clarify their potentials as blood biomarkers of the disease. Fourteen cases of lymphangiomyomatosis (LAM) were also included to compare their clinical characteristics with those of subjects with MMPH. RESULTS: Of the 9 patients, 7 were female and 2 were male. The median age at diagnosis was 43 years (range, 19-56), and all cases were diagnosed following incidental abnormal radiographic findings. During the follow-up, 1 patient died of lung cancer, but others were radiographically stable and had stable pulmonary function. Serum levels of SP-A in 5 patients (mean, 146.4 ng/mL) and SP-D in 6 patients (mean, 337.3 ng/mL) were elevated in subjects with MMPH, whereas KL-6 levels were within the reference range (mean, 230 U/mL) in all patients. Levels of SP-A and SP-D were significantly higher in subjects with MMPH than those with LAM (p < 0.05). CONCLUSIONS: Radiographic findings and pulmonary function were stable in all cases of MMPH. Serum SP-A and SP-D, but not KL-6, may be useful markers for suspicion of the presence of MMPH in patients with TSC.

Contribution of Tumor Endothelial Cells in Cancer Progression.

Tumor progression depends on the process of angiogenesis, which is the formation of new blood vessels. These newly formed blood vessels supply oxygen and nutrients to the tumor, supporting its progression and providing a gateway for tumor metastasis. Tumor angiogenesis is regulated by the balance between angiogenic activators and inhibitors within the tumor microenvironment. Because the newly formed tumor blood vessels originate from preexisting normal vessels, tumor blood vessels, and tumor endothelial cells (TECs) have historically been considered to be the same as normal blood vessels and endothelial cells; however, evidence of TECs’ distinctive abnormal phenotypes has increased. In addition, it has been revealed that TECs constitute a heterogeneous population. Thus, TECs that line tumor blood vessels are important targets in cancer therapy. We have previously reported that TECs induce cancer metastasis. In this review, we describe recent studies on TEC abnormalities related to cancer progression to provide insight into new anticancer therapies.