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Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor.

ABSTRACT: The liver is the most common site of adenocarcinoma metastases, even in patients who initially present with early disease. We postulated that immune-suppressive cells in the liver of tumor-bearing hosts inhibit anti-tumor T cells, thereby accelerating the growth of liver metastases. Using models of early preinvasive pancreatic neoplasia and advanced colorectal cancer, aims of this study were to determine immune phenotype, stimulus for recruitment, inhibitory effects, and tumor-enabling function of immune-suppressive cells in the liver of tumor-bearing hosts. We found that in mice with intra-abdominal malignancies, two distinct CD11b(+)Gr1(+) populations with divergent phenotypic and functional properties accumulate in the liver, becoming the dominant hepatic leukocytes. Their expansion is contingent on tumor expression of KC. These cells are distinct from CD11b(+)Gr1(+) populations in other tissues of tumor-bearing hosts in terms of cellular phenotype and cytokine and chemokine profile. Liver CD11b(+)Gr1(+) cells are highly suppressive of T cell activation, proliferation, and cytotoxicity and induce the development of Tregs. Moreover, liver myeloid-derived suppressor cells accelerate the development of hepatic metastases by inactivation of cytotoxic T cells. These findings may explain the propensity of patients with intra-abdominal cancers to develop liver metastases and suggest a promising target for experimental therapeutics.

SUBMITTER: Connolly MK

PROVIDER: S-EPMC2858308 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor.

Connolly Michael K MK Mallen-St Clair Jon J Bedrosian Andrea S AS Malhotra Ashim A Vera Valery V Ibrahim Junaid J Henning Justin J Pachter H Leon HL Bar-Sagi Dafna D Frey Alan B AB Miller George G

Journal of leukocyte biology 20091230 4

The liver is the most common site of adenocarcinoma metastases, even in patients who initially present with early disease. We postulated that immune-suppressive cells in the liver of tumor-bearing hosts inhibit anti-tumor T cells, thereby accelerating the growth of liver metastases. Using models of early preinvasive pancreatic neoplasia and advanced colorectal cancer, aims of this study were to determine immune phenotype, stimulus for recruitment, inhibitory effects, and tumor-enabling function ...[more]

PMID: 20042467

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Project description:Desmoid fibromatosis is a rare but locally aggressive tumor comprised of myofibroblasts. Desmoids do not have the ability to metastasize but can cause significant morbidity and mortality by local invasion. These tumors may occur throughout the body, but are commonly found on the abdominal wall and within the intestinal mesentery. Desmoids in these areas may cause unique clinical problems for physicians and patients. Mutations in either the β-catenin or the APC genes are usually the cause for the development of these tumors with the former comprising the sporadic development of tumors and the latter being associated with familial adenomatous polyposis syndrome. Surgical resection with histologically negative margins has been the cornerstone of therapy for this disease, but this paradigm has begun to shift. It is now common to accept a microscopically positive margin after resection as recurrence rates may not be significantly affected. An even more radical evolution in management has been the recent movement towards "watchful waiting" when new desmoids are diagnosed. As the natural history of desmoids has become better understood, it is evident that some tumors will not grow and may even spontaneously regress sparing patients the morbidity of more aggressive therapy. Other modalities of treatment for desmoids include radiation and systemic therapy which both can be used adjuvantly or as definitive therapy and have shown durable response rates as single therapy regimens. The decision to use radiation and/or systemic therapies is often based on tumor biology, tumor location, surgical morbidity, and patient preference. Systemic therapy options have increased to include hormonal therapies, non-steroidal anti-inflammatory drugs and chemotherapy, as well as targeted therapies. Unfortunately, the rarity of this disease has resulted in a scarcity of randomized trials to evaluate any of these therapies emphasizing the need for this disease to be treated at high volume multidisciplinary institutions.

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Project description:BackgroundThe intra-abdominal pressure (IAP) is an important clinical parameter that can significantly change during respiration. Currently, IAP is recorded at end-expiration (IAPee), while continuous IAP changes during respiration (?IAP) are ignored. Herein, a novel concept of considering continuous IAP changes during respiration is presented.MethodsBased on the geometric mean of the IAP waveform (MIAP), a mathematical model was developed for calculating respiratory-integrated MIAP (i.e. MIAPri=IAPee+i??IAP), where 'i' is the decimal fraction of the inspiratory time, and where ?IAP can be calculated as the difference between the IAP at end-inspiration (IAPei) minus IAPee. The effect of various parameters on IAPee and MIAPri was evaluated with a mathematical model and validated afterwards in six mechanically ventilated patients. The MIAP of the patients was also calculated using a CiMON monitor (Pulsion Medical Systems, Munich, Germany). Several other parameters were recorded and used for comparison.ResultsThe human study confirmed the mathematical modelling, showing that MIAPri correlates well with MIAP (R2 = 0.99); MIAPri was significantly higher than IAPee under all conditions that were used to examine the effects of changes in IAPee, the inspiratory/expiratory (I:E) ratio, and ?IAP (P <0.001). Univariate Pearson regression analysis showed significant correlations between MIAPri and IAPei (R = 0.99), IAPee (R = 0.99), and ?IAP (R = 0.78) (P <0.001); multivariate regression analysis confirmed that IAPee (mainly affected by the level of positive end-expiratory pressure, PEEP), ?IAP, and the I:E ratio are independent variables (P <0.001) determining MIAP. According to the results of a regression analysis, MIAP can also be calculated asMIAP=-0.3+IAPee+0.4??IAP+0.5?IE.ConclusionsWe believe that the novel concept of MIAP is a better representation of IAP (especially in mechanically ventilated patients) because MIAP takes into account the IAP changes during respiration. The MIAP can be estimated by the MIAPri equation. Since MIAPri is almost always greater than the classic IAP, this may have implications on end-organ function during intra-abdominal hypertension. Further clinical studies are necessary to evaluate the physiological effects of MIAP.

Project description:BackgroundMost uterine cervical high-risk human papillomavirus (HPV) infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies (GWASs) report associations between the HLA region and cervical cancer. Adopting a genome-wide approach, we aimed to compare genetic variation in women with invasive cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 with that in healthy controls.MethodsWe did a GWAS in a cohort of unrelated European individuals using data from UK Biobank, a population-based cohort including 273 377 women aged 40-69 years at recruitment between March 13, 2006, and Oct 1, 2010. We used an additive univariate logistic regression model to analyse genetic variants associated with invasive cervical cancer or CIN3. We sought replication of candidate associations in FinnGen, a large independent dataset of 128 123 individuals. We also did a two-sample mendelian randomisation approach to explore the role of risk factors in the genetic risk of cervical cancer.FindingsWe included 4769 CIN3 and invasive cervical cancer case samples and 145 545 control samples in the GWAS. Of 9 600 464 assayed and imputed single-nucleotide polymorphisms (SNPs), six independent variants were associated with CIN3 and invasive cervical cancer. These included novel loci rs10175462 (PAX8; odds ratio [OR] 0·87, 95% CI 0·84-0·91; p=1·07 × 10-9) and rs27069 (CLPTM1L; 0·88, 0·84-0·92; p=2·51 × 10-9), and previously reported signals at rs9272050 (HLA-DQA1; 1·27, 1·21-1·32; p=2·51 × 10-28), rs6938453 (MICA; 0·79, 0·75-0·83; p=1·97 × 10-17), rs55986091 (HLA-DQB1; 0·66, 0·60-0·72; p=6·42 × 10-28), and rs9266183 (HLA-B; 0·73, 0·64-0·83; p=1·53 × 10-6). Three SNPs were replicated in the independent Finnish dataset of 1648 invasive cervical cancer cases: PAX8 (rs10175462; p=0·015), CLPTM1L (rs27069; p=2·54 × 10-7), and HLA-DQA1 (rs9272050; p=7·90 × 10-8). Mendelian randomisation further supported the complementary role of smoking (OR 2·46, 95% CI 1·64-3·69), older age at first pregnancy (0·80, 0·68-0·95), and number of sexual partners (1·95, 1·44-2·63) in the risk of developing cervical cancer.InterpretationOur results provide new evidence for the genetic susceptibility to cervical cancer, specifically the PAX8, CLPTM1L, and HLA genes, suggesting disruption in apoptotic and immune function pathways. Future studies integrating host and viral, genetic, and epigenetic variation, could further elucidate complex host-viral interactions.FundingNIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme.

Dataset Information

Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor.

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Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor.

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