During the gastrulation stage in animal embryogenesis, the cells leading the axial mesoderm migrate toward the anterior side of the embryo, vigorously extending cell protrusions such as lamellipodia. ...It is thought that the leading cells sense gradients of chemoattractants emanating from the ectodermal cells and translate them to initiate and maintain the cell movements necessary for gastrulation. However, it is unclear how the extracellular information is converted to the intracellular chemical reactions that lead to motion. Here we demonstrated that intracellular Ca
levels in the protrusion-forming leading cells are markedly higher than those of the following cells and the axial mesoderm cells. We also showed that inhibiting the intracellular Ca
significantly retarded the gastrulation cell movements, while increasing the intracellular Ca
with an ionophore enhanced the migration. We further found that the ionophore treatment increased the active form of the small GTPase Rac1 in these cells. Our results suggest that transient intracellular Ca
signals play an essential role in the active cell migration during gastrulation.
We tested cis-ApcΔ716/Smad4
+/− and cis-ApcΔ716/Smad4
+/−
KrasG12D
mice, which recapitulate key genetic abnormalities accumulating during colorectal cancer (CRC) tumorigenesis in humans, for ...responsiveness to anti-VEGF therapy. We found that even tumors in cis-ApcΔ716/Smad4
+/−
KrasG12D
mice, although highly aggressive, were suppressed by anti-VEGF treatment. We tested the hypothesis that inflammation, a major risk factor and trigger for CRC, may affect responsiveness to anti-VEGF. Chemically induced colitis (CIC) in cis-ApcΔ716/Smad4
+/− and cis-ApcΔ716/Smad4
+/−
KrasG12D
mice promoted development of colon tumors that were largely resistant to anti-VEGF treatment. The myeloid growth factor G-CSF was markedly increased in the serum after induction of colitis. Antibodies blocking G-CSF, or its target Bv8/PROK2, suppressed tumor progression and myeloid cell infiltration when combined with anti-VEGF in CIC-associated CRC and in anti-VEGF-resistant CRC liver metastasis models. In a series of CRC specimens, tumor-infiltrating neutrophils strongly expressed Bv8/PROK2. CRC patients had significantly higher plasma Bv8/PROK2 levels than healthy volunteers and high plasma Bv8/PROK2 levels were inversely correlated with overall survival. Our findings establish Bv8/PROK2 as a translational target in CRC, in combination with anti-VEGF agents.
Objective Thrombocytosis can occur as a primary event accompanying hematological diseases or as a secondary event. Since the publication of the World Health Organization classification in 2008, ...thrombocytosis is now generally defined as a platelet count above 450×109/L. Furthermore, the discovery of driver-gene mutations in myeloproliferative neoplasms (MPNs) has simplified the diagnostic approach for thrombocytosis. To identify the causes of thrombocytosis using this new definition, we conducted a retrospective study. Methods We identified outpatients and inpatients aged 20 years or older with platelet counts >450×109/L in a half-year period at a single institute and analyzed the causes of thrombocytosis and associated clinical characteristics. Results Among 1,202 patients with thrombocytosis, 150 (12.5%) had primary and 999 (83.1%) had secondary thrombocytosis. Of these patients with primary thrombocytosis, 129 (86%) had at least 1 molecular marker indicative of MPNs. The major causes of secondary thrombocytosis were tissue injury (32.2%), infection (17.1%), chronic inflammatory disorders (11.7%) and iron deficiency anemia (11.1%). The median platelet count and the incidence of thrombosis were significantly higher in patients with primary thrombocytosis than in those with secondary thrombocytosis. Conclusion Thrombocytosis mainly occurs as a secondary event; however, it is important to determine the cause of and prevent thrombosis, particularly in cases of primary thrombocytosis.
Gastrulation is a dynamic tissue-remodeling process occurring during early development and fundamental to the later organogenesis. It involves both chemical signals and physical factors. Although ...much is known about the molecular pathways involved, the roles of physical forces in regulating cellular behavior and tissue remodeling during gastrulation have just begun to be explored. Here, we characterized the force generated by the leading edge mesoderm (LEM) that migrates preceding axial mesoderm (AM), and investigated the contribution of LEM during Xenopus gastrulation. First, we constructed an assay system using micro-needle which could measure physical forces generated by the anterior migration of LEM, and estimated the absolute magnitude of the force to be 20–80nN. Second, laser ablation experiments showed that LEM could affect the force distribution in the AM (i.e. LEM adds stretch force on axial mesoderm along anterior–posterior axis). Third, migrating LEM was found to be necessary for the proper gastrulation cell movements and the establishment of organized notochord structure; a reduction of LEM migratory activity resulted in the disruption of mediolateral cell orientation and convergence in AM. Finally, we found that LEM migration cooperates with Wnt/PCP to form proper notochord.
These results suggest that the force generated by the directional migration of LEM is transmitted to AM and assists the tissue organization of notochord in vivo independently of the regulation by Wnt/PCP. We propose that the LEM may have a mechanical role in aiding the AM elongation through the rearrangement of force distribution in the dorsal marginal zone.
•The role of physical force generated by leading-edge mesoderm (LEM) was examined.•The LEM-generated physical force was directly measured.•The LEM exerted a pulling force on the subsequent axial mesoderm during gastrulation.•Reduction of the LEM′s migratory activity caused abnormal notochord formation.•The LEM generated force cooperates with Wnt/PCP to form proper notochord.
We previously reported that loss of SMAD4 promotes chemokine CCL15 expression to recruit CCR1(+) myeloid cells via the CCL15-CCR1 axis, which facilitates metastasis of colorectal cancer to the liver. ...The purposes of this study were to investigate whether essentially the same mechanism works in tumor invasion of the primary colorectal cancer and to evaluate the clinical importance of CCL15 expression and CCR1(+) cell accumulation.
Using human colorectal cancer cell lines with reduced expression of SMAD4 or CCL15, we investigated tumor growth activities in vivo. We used immunohistochemistry (IHC) to investigate expression of SMAD4, CCL15, and CCR1 with 333 clinical specimens of primary colorectal cancer. We next characterized the CCR1(+) cells using double immunofluorescence staining with several specific cell-type markers. Finally, we determined the serum CCL15 levels in 132 colorectal cancer patients.
In an orthotopic xenograft model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1(+) cells, resulting in aggressive tumor growth. IHC indicated that loss of SMAD4 was significantly associated with CCL15 expression, and that CCL15-positive primary colorectal cancers recruited approximately 2.2 times more numbers of CCR1(+) cells at their invasion front than CCL15-negative colorectal cancers. Importantly, these CCR1(+) cells were of the myeloid-derived suppressor cell (MDSC) phenotype (CD11b(+), CD33(+), and HLA-DR(-)). Most CCR1(+) cells showed the granulocytic-MDSC phenotype (CD15(+)), whereas some showed the monocytic-MDSC phenotype (CD14(+)). Serum CCL15 levels in colorectal cancer patients were significantly higher than in controls.
Blocking the recruitment of CCR1(+) MDSCs may represent a novel molecular-targeted therapy, and serum CCL15 concentration can be a novel biomarker for colorectal cancer.
Healthcare workers (HCWs) are highly exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The actual coronavirus disease (COVID-19) situation, especially in regions that ...are less affected, has not yet been determined. This study aimed to assess the seroprevalence of SARS-CoV-2 in HCWs working in a frontline hospital in Tokyo, Japan. In this cross-sectional observational study, screening was performed on consented HCWs, including medical, nursing, and other workers, as part of a mandatory health checkup. The screening test results and clinical characteristics of the participants were recorded. The antibody seroprevalence rate among the 4147 participants screened between July 6 and August 21, 2020, was 0.34% (14/4147). There was no significant difference in the seroprevalence rate between frontline HCWs with a high exposure risk and HCWs working in other settings with a low exposure risk. Of those seropositive for SARS-CoV-2, 64% (9/14) were not aware of any symptoms and had not previously been diagnosed with COVID-19. In conclusion, this study provides insights into the extent of infection and immune status in HCWs in Japan, which has a relatively low prevalence of COVID-19. Our findings aid in formulating public health policies to control virus spread in regions with low-intensity COVID-19.
In 2020, we reported a low seroprevalence of N-specific antibodies in 4147 health care workers (HCWs) at a frontline hospital in Tokyo, Japan. In Japan, a vaccine campaign was launched in early 2021. ...We re-evaluated seroprevalences of N- and S-specific antibodies in 2202 HCWs who took two doses of the BNT162b2 vaccine. In 2021, N-specific seroprevalence remains as low as 1.59%. The seroprevalences were comparable among all HCWs regardless of exposure levels. Almost all of the HCWs elicited S-specific antibodies after vaccination. However, the HCWs who had COVID-19 elicited higher S-specific antibody titers than those who did not have COVID-19. In the HCWs without a history of COVID-19, 1.1% (23 out of 2185) were seropositive with N-specific antibodies, indicating the existence of asymptomatic infections. Also, S-specific antibody titers were higher in females and younger HCWs, and in those who had severe side effects. However, S-specific antibody titers were lower depending on the number of days after the second dose of vaccination specifically in elderly individuals. In conclusion, this study indicates N-specific seroprevalence remains low in HCWs at a frontline hospital in Tokyo. The mRNA vaccine elicited S-specific antibody in HCWs, however, the titers decreased as the days proceeded.
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Although most of the primary CRC can be removed by surgical resection, advanced tumors sometimes show ...recurrences in distant organs such as the liver, lung, lymph node, bone or peritoneum even after complete resection of the primary tumors. In these advanced and metastatic CRC, it is the tumor-stroma interaction in the tumor microenvironment that often promotes cancer invasion and/or metastasis through chemokine signaling. The tumor microenvironment contains numerous host cells that may suppress or promote cancer aggressiveness. Several types of host-derived myeloid cells reside in the tumor microenvironment, and the recruitment of them is under the control of chemokine signaling. In this review, we focus on the functions of chemokine signaling that may affect tumor immunity by recruiting several types of bone marrow-derived cells (BMDC) to the tumor microenvironment of CRC.
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