Lactoferrin deficiency induces a pro-metastatic tumor microenvironment through recruiting myeloid-derived suppressor cells in mice
Authors: Qiu Peng
Zhengshuo Li
Peishan Liu
Qiurong Ye
Ying Zheng
Xiaoyue Zhang
Guiyuan Li
Jian Ma
Can Liu
Xuemei Zhang
Jia Wang
Qun Yan
Lingyu Wei
Xiang Zheng
Journal: Oncogene (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Lactoferrin; innate immunity; anti-inflammatory; anti-microbial; anti-tumor activities
Affiliations: Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Third Xiangya Hospital, Central South University, Changsha, China., Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China., Key Laboratory of Carcinogenesis of Ministry of Health, Changsha, China., Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha, China., Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China., Center for Medical Research, Second Xiangya Hospital, Central South University, Changsha, China., Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China., Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Third Xiangya Hospital, Central South University, Changsha, China. ., Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China. ., Key Laboratory of Carcinogenesis of Ministry of Health, Changsha, China. ., Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha, China. ., Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. .

Abstract:  Lactoferrin, an innate immunity molecule, is involved in anti-inflammatory, anti-microbial, and anti-tumor activities. We previously reported that lactoferrin is downregulated in specimens of nasopharyngeal carcinoma and negatively associated with tumor progression and metastasis of patients with nasopharyngeal carcinoma. However, the relationship between lactoferrin and the pro-metastatic microenvironment has not been reported yet. Here, by using the lactoferrin knockout mouse, we found that lactoferrin deficiency facilitated melanoma cells metastasizing to lungs, through recruiting myeloid-derived suppressor cells (MDSCs) in the lungs. Mechanistic studies showed that in the lung microenvironment of the lactoferrin knockout mice, the TLR9 signaling was the most repressed signaling. Lactoferrin can induce MDSCs differentiation and apoptosis, as well as upregulate TLR9 expression. TLR9 agonist or lactoferrin treatment can rescue this phenotype in the tumor metastasis mouse model. Our results suggest a protective role of lactoferrin in cancer metastasis, along with a deficiency in certain components of the innate immune system, may lead to a pro-metastatic tumor microenvironment. 

Retracted: No

PubPeer comments:
  Figure 3. Different FTu2013IR spectra with an ATR attachment of BUD, PLGA, PVA, chitosan, physical mixture, and freeze-dried CS-coated-BUDu2013PLGAu2013NPs. ![file] The spectrum for BUD (lowest) does not appear to have been plotted under the same circumstances as those for the other materials. , 
 In Fig 8b, the regression line does not really look like a least-squares best fit to the data points. Could the authors check? ![file] H t @IncredibleChem: https: twitter.com IncredibleChem status 1264667926268907523 , 
 Even the labelling is wrong: ![file] , 
 I have some more to add: In Figure 1A, the size distribution of the nanoparticles shows a median diameter of approx 200 nm, but in the SEM image in Figure 1C, the diameter is 20-100 u00b5M. In the TEM image in Figure 1D, the size is back to approx 100 nm, but the ultrastructure is very different from the perfect circular structure shown by SEM. ![file] , 
 #1 BUD spectrum was taken when we started the study as a preformulation study and authentication of pure standard drug. Rest of them was taken when formulation was optimized. Therefore, it is looking different. , 
 #2 Yes, the authors have checked it properly. It is correctly mentioned. , 
 #3 The labeling is completely correct. May be due to zoom-in for the picture the line seems an ink-spreader-image and the digits are gone shifted a bit. However, none of the value is wrong or with an error. The image was re-checked and validated. , 
 @Niyaz Ahmad I suggest you provide the original (raw) files for the data discussed here, so everyone can be as sure as you are that the data is  re-checked and validated . , 
 #4 SEM is performed to observe the shape of particles and generally it measures in micrometer whereas TEM is used to measure particle size. Now in the image Figure 1D, the particle size was less than 100 although the scale is up to 200 or 500, it does not matter if your results are within the specified range. Our particle size was less than 200 and that is what needs to be focused. Thank you , 
 Retracted [11 January 2021] . --------------------------------------- We, the Editors and Publishers of Artificial Cells, Nanomedicine, and Biotechnology have retracted the following article: Niyaz Ahmad, Rizwan Ahmad, Mortaja Zaki Almakhamel, Khalid Ansari, Mohd Amir, Wasim Ahmad, Abuzer Ali Farhan Jalees Ahmad. (2020). A comparative pulmonary pharmacokinetic study of budesonide using polymeric nanoparticles targeted to the lungs in treatment of asthma. Artificial Cells, Nanomedicine, and Biotechnology, 48:1, 749u2013762. DOI: 10.1080 21691401.2020.1748640 This article is retracted due to concerns raised regarding the integrity of Figures in the article, including Figures 1, 3, and 10. When asked for an explanation, the authors were unable to provide a satisfactory explanation or the raw data that would support the integrity of their research. Because of this, the Editors agreed the findings of the study are no longer valid and advised for the article to be retracted. The authors do not agree with the retraction. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as u201cRetractedu201d. ,