Hepatic metastatic niche: from normal to pre-metastatic and metastatic niche

Liver is the organ responsible for hematopoiesis during fetal life, which is also a target organ of metastasis for several cancers. In order to recognize the hepatic metastatic changes, obtain a better grasp of cancer prevention, treatment, and inhibition mode of hepatic metastasis progression, we investigate the changes and transformation of normal hepatic niche cells to metastatic niche ones in this review. On the other hand, since metastatic diseases alter the liver function, the changes in a number of cancers that metastasize to the liver have also been reviewed. Relevant English-language literature was searched and retrieved from PubMed (1994–2014) using the following keywords: hepatic stem cell niche, hepatic metastatic niche, chemokine, and microRNAs (miRNAs). Also, over 86 published studies were investigated, and bioinformatics analysis of differentially expressed miRNAs in hepatic cancer and metastasis was performed. Metastasis is developed in several stages with specific changes and mechanisms in each stage. Recognition of these changes would lead to detection of new biomarkers and clinical targets involved in specific stages of liver metastasis. Investigation of the hepatic stem cell niche, development of metastasis in liver tissue, as well as changes in chemokines and miRNAs in metastatic hepatic niche can significantly contribute to faster detection of liver metastasis progression.     

Oncogenes and metastatic progression

It is now established that ras oncogenes can induce metastatic characteristics in primary diploid fibroblasts, nonsenescing fibroblasts and nonmetastasizing tumors. The issue of whether ras is directly involved in maintaining the metastatic phenotype through the expression and action of its gene product has been examined by analyzing the relationship to ras expression and to the production of the p21 ras-GTP complex, which is thought to mediate ras-transforming activity. While these expression and mutation studies support the idea that p21 ras directly regulates metastasis formation, it is also evident that there are many examples of human and murine cancers which show no differences in ras expression in primary and metastatic tumor cells. This may be partially explained by the ability of protein kinase-encoding oncogenes to also induce metastatic potential. In addition, the ability of ras to induce metastasis may be dependent on the regulation of its activity by other genes. Furthermore, transformation does not occur as an isolated genetic event, but is rather the result of interaction of two or more oncogenes. We suggest that the nature of these gene interactions will ultimately determine whether a cell is a benign transformant or a malignant and metastatic cancer.     

A TeNaCious foundation for the metastatic niche

In the July issue of Nature Medicine, Massagué and colleagues define a biphasic role for the extracellular matrix protein tenascin C as a metastatic niche component in lung colonization by breast cancer cells. These results provide a rationale for designing therapies targeting metastatic progression by disrupting its very foundations.     

Splenectomy reduces lung metastases and tumoral and metastatic niche inflammation

The immune microenvironment plays a crucial role in supporting tumor growth and metastasis. Tumor-associated macrophages (TAMs) and neutrophils (TANs) are essential components of this microenvironment and affect tumor growth and progression in almost all solid neoplasms. Furthermore, TAMs, TANs and tumor-infiltrating dendritic cells (TIDCs) are found to infiltrate specific distant organs to prepare them as a site for metastatic cell seeding, forming the pre-metastatic niche. The spleen was identified as a major reservoir and source of circulating and tumor infiltrating immune cells. However, discrepancies about its role in supporting tumor growth exist. Thus, here we investigated the role of splenectomy in primary tumor and metastatic growth, and in the formation of an inflammatory niche. In a murine 4T1 and E0771 breast and Panc02 pancreatic cancer model, our results show that while splenectomy reduces the number of infiltrating TAMs, TANs and TIDCs within primary tumors, it does not affect its growth. In line, fewer TAMs, TANs and TIDCs accumulate in the metastatic microenvironment after splenectomy. Interestingly though, this affected metastatic growth depending on the metastatic route/site. The number of hematogenous breast cancer lung metastases was reduced after splenectomy but no effect was observed in breast or pancreatic lymph node metastases. Moreover, we observed that the immune composition of the pre-metastatic niche in lungs of breast cancer bearing mice was altered, and that this could cause the reduction of metastases. Altogether, our results highlight that splenectomy affects the immune microenvironment not only of primary tumors but also of pre-metastatic and metastatic sites.     

Genetic progression of metastatic melanoma

Melanoma progression is well defined in its clinical, histopathological and biological aspects, but the molecular mechanism involved and the genetic markers associated to metastatic dissemination are only beginning to be defined. The recent development of high-throughput technologies aimed at global molecular profiling of cancer is switching on the spotlight at previously unknown candidate genes involved in melanoma, such as WNT5A and BRAF. In fact, several tumor suppressors and oncogenes have been shown to be involved in melanoma pathogenesis, including CDKN2A, PTEN, TP53, RAS and MYC, though they have not been related to melanoma subtypes or validated as prognostic markers. Here, we have reviewed the published data relative to the major genes involved in melanoma pathogenesis, which may represent important markers for the identification of genetic profiles of melanoma subtypes.     

Examining the metastatic niche: targeting the microenvironment

Some of the most common cancer types, including breast cancer, prostate cancer, and lung cancer, show a predilection to metastasize to bone. The molecular basis of this preferential growth of cancer cells in the bone microenvironment has been an area of active investigation. Although the precise molecular mechanisms underlying this process remain to be elucidated, it is now increasingly being recognized that the unique characteristics of the bone niche provide homing signals to cancer cells, and create a microenvironment conducive for the cancer cells to colonize. Concomitantly, cancer cells release several regulatory factors that result in abnormal bone destruction and/or formation. This complex bidirectional interplay between tumor cells and bone microenvironment establishes a "vicious cycle" that leads to a selective growth advantage for the cancer cells. The molecular insights gained on the underpinnings of bone metastasis in recent years have also provided us with avenues to devise innovative approaches for therapeutic intervention. The goal of this review is to describe our current understanding of molecular pathophysiology of cancer metastases to bone, as well as its therapeutic implications.     

Germ line polymorphism in metastatic progression

Somatic genetic analysis of tumors and metastases has yielded a plethora of information regarding genes associated with cancer progression. However, somatic alterations in tumor cells are only one source of variability. Genetic polymorphism may also play a significant role in person-to-person variability in metastasis frequency, raising the intriguing possibility that some individuals could be predisposed to secondary tumor development. The identification and characterization of these polymorphisms may have significant implications for the development of tailored treatment or prevention of recurrent disease.     

The landscape of metastatic progression patterns across major human cancers

The majority of patients with solid malignancies die from metastatic burden. However, our current understanding of the mechanisms and resulting patterns of dissemination is limited. Here, we analyzed patterns of metastatic progression across 16 major cancer types in a cohort of 1008 patients with metastatic cancer autopsied between 2000 and 2013 to assess cancer specific progression patterns of disease and related risk predictions. The frequency and location of metastases were evaluated in and across 1) 16 major cancers, 2) smoking- and non-smoking-related cancers and 3) adeno- and squamous cell carcinoma. Associations between primary and secondary sites were analyzed by the fractional and the relative risk methods. We detected significantly different cancer specific patterns of metastatic progression with specific relative risk profiles for secondary site involvement. Histology and smoking etiology influenced these patterns. Backward analysis showed that metastatic patterns help to predict unknown primary sites. Solid malignancies maintain a unique and recurrent organ tropism to specific secondary sites which does not appear to be strongly influenced by advances in cancer medicine as shown by comparison with previous data sets. The delineated landscape of metastatic progression patterns is a comprehensive data resource to both clinical and basic scientists which aids fostering new hypotheses for cancer research and cancer therapies.     

Spontaneous regression of metastatic endometrial stromal sarcoma

Spontaneous regression of malignancy is rare and there appear to be no reports of spontaneous regression of endometrial stromal sarcoma. We report a rare case of metastatic endometrial stromal sarcoma that regressed spontaneously. A 58-year-old woman was admitted to hospital in January 1996 when her chest radiograph showed multiple nodular shadows in the left lower lung field. Computed tomography of the chest revealed bilateral nodules. Segmentectomy of the left lower lobe was performed by thoracoscopy. She had a past history of uterine myoma with metrorrhagia for which she had undergone a hystero-oophorectomy 10 years earlier. She also had a vaginal polyp removed 1 year earlier. The lung pathology was studied and the surgical specimens of the uterus and vagina were re-examined. The diagnosis was endometrial stromal sarcoma primarily arising in the uterus. The vaginal polyp and the pulmonary nodules were considered to be metastases. Samples of lung and vaginal tissues were positive for both estrogen and progesterone receptors. The patient was discharged without treatment in February 1996 and followed up in the outpatient clinic. The tumor shadow measuring 2 mm in diameter on admission was enlarged to 4 mm in diameter 1 year later. Surprisingly, spontaneous regression of the lung disease occurred at 33 months, the tumor size decreasing to 2 mm in diameter and to 1 mm at 46 months. No evidence of tumor enlargement was detected at the last follow-up in July 2001. Although the precise mechanism of tumor regression is unknown, metastatic endometrial stromal sarcoma may spontaneously regress.     

Cancer-associated stromal fibroblasts promote pancreatic tumor progression

Pancreatic adenocarcinoma is characterized by a dense background of tumor associated stroma originating from abundant pancreatic stellate cells. The aim of this study was to determine the effect of human pancreatic stellate cells (HPSC) on pancreatic tumor progression. HPSCs were isolated from resected pancreatic adenocarcinoma samples and immortalized with telomerase and SV40 large T antigen. Effects of HPSC conditioned medium (HPSC-CM) on in vitro proliferation, migration, invasion, soft-agar colony formation, and survival in the presence of gemcitabine or radiation therapy were measured in two pancreatic cancer cell lines. The effects of HPSCs on tumors were examined in an orthotopic murine model of pancreatic cancer by co-injecting them with cancer cells and analyzing growth and metastasis. HPSC-CM dose-dependently increased BxPC3 and Panc1 tumor cell proliferation, migration, invasion, and colony formation. Furthermore, gemcitabine and radiation therapy were less effective in tumor cells treated with HPSC-CM. HPSC-CM activated the mitogen-activated protein kinase and Akt pathways in tumor cells. Co-injection of tumor cells with HPSCs in an orthotopic model resulted in increased primary tumor incidence, size, and metastasis, which corresponded with the proportion of HPSCs. HPSCs produce soluble factors that stimulate signaling pathways related to proliferation and survival of pancreatic cancer cells, and the presence of HPSCs in tumors increases the growth and metastasis of these cells. These data indicate that stellate cells have an important role in supporting and promoting pancreatic cancer. Identification of HPSC-derived factors may lead to novel stroma-targeted therapies for pancreatic cancer.     

Surgical resection in metastatic gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract. Traditionally, surgery has been the primary treatment modality for these tumors, with only modest results. The recent development of kinase inhibitors (most notably, imatinib mesylate) has provided a new paradigm for the treatment of this disease. Response rates approaching 60% have been seen in studies in patients with advanced disease. Previously, chemotherapy played little role in the treatment of this disease. Now, however, treatment with kinase inhibitors can increase the number of patients who may potentially benefit from surgical intervention. Many questions regarding the use of kinase inhibitors remain. Most importantly, the optimal duration of treatment before surgical intervention and following both complete and incomplete tumor resection remains to be elucidated. Ongoing prospective trials have the potential to provide some of these answers in the near future.     

Surgical management of metastatic gastrointestinal stromal tumour

Background

Gastrointestinal stomal tumours (GISTs) are the most frequently diagnosed mesenchymal tumour of the gastrointestinal tract. The response of most GISTs to tyrosine kinase inhibitor (TKIs) treatment is spectacular; however progression and/or secondary resistance inevitably occurs with long-term treatment of recurrent or metastatic disease. Randomised studies investigating the potential additive benefit of metastasectomy in addition to TKI treatment unfortunately failed to accrue sufficient patients. Therefore, the apparent benefit of surgery in the setting of metastatic disease is based on retrospective institutional series or extrapolation of data from studies which were not intended directly to investigate the impact of surgery. The aim of this review is to summarise the current literature to inform an approach to the surgical management of metastatic GIST.

Stromal-cell and cancer-cell exosomes leading the metastatic exodus for the promised niche

Exosomes are thought to play an important role in metastasis. Luga and colleagues have described the production of exosomes by stromal cells such as cancer-associated fibroblasts that are taken up by breast cancer cells and are then loaded with Wnt 11, which is associated with stimulation of the invasiveness and metastasis of the breast cancer cells. Previous studies have shown that exosomes produced by breast cancer cells are taken up by stromal fibroblasts and other stromal cells, suggesting that exosomes are agents of cross-talk between cancer and stromal cells to stimulate metastasis. Imaging of exosomes by labeling with fluorescent proteins will enlighten the process by which exosomes enhance metastasis, including premetastatic niche formation.Exosomes are small (30 to 100 nm) membrane vesicles that originate from the endosomal membrane compartment [1-3]. Exosomes contain mRNAs, miRNAs and proteins, and possibly other components as well [1,4,5]. Cancer cells release exosomes into the tumor microenvironment and peripheral blood [1,6].Do stromal cells in the tumor microenvironment also produce exosomes that stimulate cancer metastasis? We previously showed that cancer cell-associated stromal cells are necessary for metastasis to occur [7]. Luga and colleagues now report in a recent issue of Cell that stromal cells indeed produce exosomes and that fibroblast-secreted exosomes promote breast cancer cell (BCC) motility and metastasis by mobilizing autocrine Wnt11-induced planar cell polarity in the cancer cells [8]. Wnt11 is tethered to the fibroblast-derived exosomes within BCCs. Exosome stimulation of BCC invasion and metastasis was shown to be dependent on Wnt11 produced in the BCCs. Cancer-associated fibroblast (CAF)-derived exosomes were internalized by BCCs and then loaded with Wnt11 in orthotopic mouse models of breast cancer. Luga and colleagues report that exosomes secreted from human breast CAFs stimulate BCC protrusive activity, motility, and metastasis. These proper ties are dependent on the exosome-stetraspanin, Cd81, which is critical for exosome-stimulated BCC metastasis [8]. These are intriguing findings on how stromal cells promote metastasis via exosomes.Previous suggestions indicated that recruited bone marrow progenitor cells generated a premetastatic niche to which the cancer cells metastasize [9-11]. Secreted factors in the bone marrow may be important to mobilize cells to form the pre metastatic niche. Exosomes, derived from cancer cells, have recently been shown to have an important role in premetastatic niche formation [9-11]. However, Luga and colleagues do not suggest how stromal cell-derived exosomes play a role in the formation of a premetastatic niche [8].Investigating premetastatic niche formation requires the possibility for dynamic imaging of exosomes in vivo. To image the fate of cancer cell-derived exosomes in orthotopic nude mouse models of breast cancer, we used GFP-tagged CD63, which is a general marker of exosomes [12]. BCCs were imaged to transfer their own exosomes to other cancer cells and normal lung tissue cells in culture. In orthotopic nude mouse models, BCCs secreted exosomes into the tumor microenvironment. Tumor-derived exosomes were incorporated into tumorassociated cells at a metastatic site, including CAFs (Figure ​(Figure1),1), and in the circulation. These results suggest that tumor-derived exosomes may contribute to forming a niche to promote tumor growth and metastasis. Our results demonstrate the usefulness of GFP imaging to investigate the role of exosomes in cancer metastasis [12-15].Open in a separate windowFigure 1Cancer cells secrete exosomes into the tumor microenvironment in human MDA-MB-231 breast cancer orthotopic mouse models. The red fluorescent protein (RFP)-expressing MDA-MB-231-cells-produced exosomes which were labeled with a CD63-GFP fusion protein (MDA-MB-231-RFP/GFP-Exo). (A) MDA-MB-231-RFP/GFP-Exo cells secreted GFP exosomes in the primary tumor tissue. Blue arrows, MDA-MB-231-RFP/GFP-Exo cells; yellow arrows, secreted GFP exosomes. Scale bar = 100 μm. (B) MDA-MB-231-RFP/GFP-Exo cells secreted GFP exosomes at the lung colonization site. Yellow arrows, secreted GFP exosomes; blue arrows, lung metastatic MDA-MB-231-RFP/GFP-Exo cells. Scale bar = 20 μm. (C) Blue arrows, GFP-Exo incorporated in RFP stroma cells; yellow arrows, secreted GFP exosomes. Scale bar = 10 μm. (D) Blue arrows, GFP-Exo incorporated in RFP cancer-associated fibroblasts (CAFs); yellow arrows, secreted GFP exosomes. Scale bar = 10 μm [12].Both cancer cell-derived or stromal cell-derived exosomes are thus able to alter the tumor environment and may participate in forming a distant metastatic niche to promote metastasis. Dynamic imaging of exosomes derived from cancer or stromal cells in metastatic models may hence help us to understand the mechanism of cancer metastasis. Imaging of exosomes may also be useful to predict the location of future metastasis in real time.This viewpoint demonstrates the importance of exosome cross-talk between cancer cells and stromal cells. Luga and colleagues demonstrate the production of exosomes by stromal cells such as CAFs that are taken up by BCCs, which in turn promote their invasive and metastatic activity [8]. Suetsugu and colleagues demonstrate production of exosomes by BCCs that are taken up by CAFs [10], the reciprocal of what was observed by Luga and colleagues [8]. With the use of fluorescentprotein in vivo imaging [13-15], further understanding of exosomes and their relationship to metastasis, including niche formation, will surely be enlightened.     

The successful management of two pregnancies with wild type metastatic gastrointestinal stromal tumors

Aim:   To discuss the management of the uncommon situation of metastatic gastrointestinal tumour coexisting with pregnancy.
Method:   We describe two cases of women with metastatic gastrointestinal stromal tumor (GIST) who successfully achieved a full-term pregnancy without complications and with the delivery of healthy infants. In both cases, treatment with imatinib mesylate was withheld during pregnancy because of its unknown effects and questionable safety for the developing fetus. The available data in the medical literature regarding the use and safety of imatinib and pregnancy are reviewed. We also examine whether the knowledge of the exon mutational status would have influenced treatment decisions.
Results:   Both women had wild type GIST, but with different tumor growth characteristics, treatment responses and outcomes. The first patient deferred imatinib therapy to fall pregnant and her disease progressed rapidly off treatment. The second patient had a more indolent GIST where active surgical management allowed her to experience a long durable clinical response. She potentially belongs to a pediatric subgroup which carries a better prognosis despite being off imatinib.
Conclusion:   While we have successfully managed two pregnant women with metastatic GIST, the issue of initiating imatinib therapy in treatment-naive women, and treatment interruption in women already on therapy, remain difficult areas. Patients and their partners need to make an informed choice regarding the associated risks and the potential long-term sequelae if pregnancies are contemplated. Further research into the natural history of wild type GIST and how to tailor subsequent treatment are needed.     

胸腺基质淋巴细胞生成素与肿瘤发生发展的关系

胸腺基质淋巴细胞生成素（thymic stromal lymphopoietin,TSLP）是一种主要由皮肤、肺、胸腺与胃肠道等器官的上皮细胞分泌的与IL-7类似的炎性细胞因子。TSLP是一种多功能的细胞因子,可以作用于多种细胞如T细胞、B细胞、DC和肿瘤细胞等,具有重要的生物学功能。近年来,越来越多的研究表明,TSLP能够调控肿瘤的发生发展。一方面,TSLP在结肠癌、皮肤癌以及初期乳腺癌、胰腺癌的发展阶段发挥了重要的抗肿瘤作用;另一方面,TSLP在胃癌、肺癌、子宫颈癌和急性淋巴细胞白血病等恶性肿瘤的发生发展过程中发挥促进肿瘤进展的作用,提示TSLP可作为相关肿瘤治疗的潜在靶点。本文综述了近年来TSLP及其信号通路,以及其与乳腺癌、胰腺癌、子宫颈癌、胃癌、结肠癌、肺癌、皮肤癌、B细胞急性淋巴细胞白血病等多种恶性肿瘤发生发展的关系的研究进展,旨在为相关肿瘤的诊断和治疗提供新的思路。     

New functions of stromal proteases and their inhibitors in tumor progression

Acquisition of invasive metastatic potential through protease expression is a key event in tumor progression. In carcinomas, the production of metalloproteinases and serine proteinases is regulated by a cross talk between stromal cells and cancer cells. Paradoxically, high rather than low levels of their inhibitors predict poor survival of patients suffering from a variety of cancers. Recent observations suggest a much more complex role of these inhibitors in tumor progression than expected initially.