Tumor-derived lymphangiogenic factors and lymphatic metastasis.

Lymphatic endothelial cells (LECs) originally differentiated from venous endothelial cells express several specific makers that distinguish them from the blood vessels. Lymphangiogenesis, a complex process of sprouting of new lymphatic vessels, is regulated by multiple direct and indirect growth factors. Vascular endothelial growth factor-C (VEGF-C) is the most potent and selective lymphangiogenic factor that plays a crucial role in the establishment of the first lymphatic vessel during embryonic development and in mediating lymphatic metastasis. In addition to VEGF-C, recent studies show that a range of known tumor-produced angiogenic factors also stimulates lymphangiogenesis, suggesting complex and tight regulations of this process. These tumor-derived lymphangiogenic factors may either alone or jointly promote lymphatic metastasis. Understanding regulatory mechanisms of lymphangiogenesis is pivotal for development of lymphangiogenesis antagonists that might therapeutically be used for intervention of lymphatic metastasis.     

Keratinocyte growth factor

Mucositis occurs in over 90% of patients undergoing stem cell transplantation for hematological malignancies. It is associated with significant morbidity in the form of pain, dysphagia and decreased oral intake, as well as mortality. Palifermin is a recombinant keratinocyte growth factor that has been shown to be effective in decreasing the incidence, severity and duration of mucositis in Phase III trials. Improvement in patient functioning during hematopoietic stem cell transplants has also been reported. This review deals with the preclinical data and the clinical trials that have been carried out with this agent in patients with hematologic malignancies. In addition limited Phase I and II data on solid tumors is available and will be included.     

神经生长因子促进烫伤创面释放内源性生长因子

背景：研究证实神经生长因子促进创面组织释放内源性各类生长因子及生长因子受体,起到正性调节作用,促进修复细胞增殖,加速创面愈合,使创面愈合由以往的被动等待自愈发展到主动调控愈合。目的：观察局部应用神经生长因子对大鼠烫伤创面转化生长因子β1和碱性成纤维细胞因子表达的影响。方法：取24只成年 SD 大鼠,于背部制成深Ⅱ度烫伤创面,随机分为4组,烧伤创面清创后,分别予以两层浸湿有1,2.5,5 mg/L 神经生长因子溶液及等渗盐水纱布覆盖。治疗后3,5,9,14 d 观察创面愈合时间和创面残留率,切取创面组织进行组织学观察,检测创面转化生长因子β1,碱性成纤维细胞因子的表达及细胞 DNA 周期的变化。结果与结论：各治疗组创面愈合时间较对照组提前,尤以5 mg/L 神经生长因子治疗组最为明显(P <0.01),各治疗组创面残留率较对照组明显减小;创面组织学显示治疗组真皮浅层有核细胞数较对照组明显增多;各治疗组给药时间点转化生长因子β1,碱性成纤维细胞因子表达均强于对照组,第5天和第9天表达强于第3天和第14天;各治疗组细胞在 S 期的百分比较对照组明显增加,其中5 mg/L 神经生长因子组增加最为显著(P <0.01)。结果显示局部应用神经生长因子可通过促进创面转化生长因子β1及碱性成纤维细胞因子表达,刺激细胞有丝分裂,促使细胞增殖,加速大鼠烫伤创面愈合。     

肥厚腰椎黄韧带中成纤维细胞生长因子、转化生长因子及结缔组织生长因子的表达

背景：腰椎黄韧带肥厚是临床上引起腰椎管狭窄的主要因素之一,但其分子机制仍不是非常清楚。目的：分析纤维化相关细胞因子碱性成纤维细胞生长因子、转化生长因子β1和结缔组织生长因子在腰椎黄韧带肥厚过程中的作用。方法：取临床手术所取黄韧带,对照组6例（椎管内占位且无腰椎不稳患者黄韧带）、突出组（单纯腰椎间盘突出症患者黄韧带）6例、腰椎管狭窄症组6例。采用实时定量RT-PCR的方法检测各组黄韧带中碱性成纤维细胞生长因子、转化生长因子β1、结缔组织生长因子及Ⅰ、Ⅲ、Ⅴ型胶原蛋白的mRNA含量,分析3个细胞因子在黄韧带肥厚过程中的作用。结果与结论：腰椎管狭窄症组碱性成纤维细胞生长因子mRNA表达均明显高于突出组和对照组（均P 〈0.05）;腰椎管狭窄症组转化生长因子β1mRNA在3组中的表达明显高于对照组和突出组（均P 〈0.01）;结缔组织生长因子 mRNA 3组间差异无显著性意义（P 〉0.05）。腰椎管狭窄症组Ⅰ型胶原蛋白mRNA表达明显高于突出组和对照组（均P 〈0.05）;Ⅲ型胶原蛋白、Ⅴ型胶原蛋白mRNA表达3组之间差异无显著性意义（P 〉0.05）。结果说明碱性成纤维细胞生长因子、转化生长因子β1在腰椎黄韧带肥厚形成过程中有重要作用,引起黄韧带肥厚的主要胶原产物为Ⅰ型胶原蛋白。     

Tumor-derived activated cells: preliminary laboratory and clinical results

It is well known that T lymphocytes can mediate significant anti-tumor responses. A limiting factor has always been the ability to expand T cells, whether from the peripheral blood, spleen, or tumor. The recent availability of recombinant interleukin-2 (r-IL2) has demonstrated the feasibility of expanding T cells and the clinical efficacy of these cells as anti-tumor effectors in murine models. Concomitantly, researchers discovered that lymphokine-activated killer cells--peripheral blood cells functionally distinct from T cells--could be cultured, expanded, and re-infused in patients, with significant clinical effects. For many years, the infiltrating lymphocytes have been recognized in tumor biopsies and known to be cytolytically active. Major limiting factors were the ability to culture large numbers of these infiltrating cells and the limited understanding of the tumor antigens involved for T-cell stimulation. Restimulation by antigen (tumor cells) appears to provide the ongoing antigen stimulation needed to maintain selective killing of tumor cells. By defining various factors in the medium that support and enhance T-cell growth and activation, the components are becoming available to develop a broad attack on advanced cancer by using this laboratory-based technology of stimulation and expansion of tumor-derived activated cells.     

A transforming growth factor beta-like immunosuppressive factor in immunoglobulin G-binding factor

Immunoglobulin G-binding factors (IgG-BF), which are produced by cells of the immune system, inhibit antibody production. In this paper, we show that transforming growth factor-beta (TGF-beta) suppresses secondary in vitro anti-sheep red blood cell responses of mouse splenocytes and lipopolysaccharide- or anti-IgM-stimulated mouse B cell responses in a way similar to, and with the same kinetics as, rodent IgG-BF. Moreover, the immunosuppressive activity of IgG-BF was totally neutralized by polyclonal and monoclonal anti-TGF-beta antibodies and it eluted with TGF-beta by gel exclusion chromatography, suggesting that a TGF-beta-like immunosuppressive factor is present in IgG-BF. We also show that TGF-beta behaves as an IgG-BF since it binds to insolubilized IgG, but not to insolubilized F(ab')2 or bovine serum albumin. Altogether, the data support the concept of a biological role for TGF-beta in the IgG-mediated negative feedback of antibody responses.     

Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo.

Keratinocyte growth factor (KGF) administered as a single intratracheal injection causes a prominent dose-dependent proliferation of type II alveolar epithelial cells in the lungs of adult rats. The increase in mitotically active alveolar cells histologically appears as a micropapillary epithelial cell hyperplasia after 2 d and peaks after 3 d in the form of monolayers of cuboidal epithelial cells lining alveolar septae. Proliferating cell nuclear antigen immunohistochemistry confirmed the profound proliferative response induced by KGF. The hyperplastic alveolar lining cells contain immunoreactive surfactant protein B and are ultrastructurally noted to contain lamellar inclusions characteristic of surfactant-producing type II pneumocytes. Mild focal bronchiolar epithelial hyperplasia is noted but is much less striking than the proliferation of type II pneumocytes. Large airways are unaffected by KGF. Daily intravenous injection of KGF is also able to cause pneumocyte proliferation. The normal adult rat lung constitutively expresses both KGF and KGF receptor mRNA, suggesting that endogenous KGF may be implicated in the paracrine regulation of the growth of pneumocytes. In conclusion, KGF rapidly and specifically induces proliferation and differentiation of type II pneumocytes in the normal adult lung.     

Lactoferrin--a novel bone growth factor

Lactoferrin is an iron-binding glycoprotein that belongs to the transferrin family. It is present in breast milk, in epithelial secretions, and in the secondary granules of neutrophils. In healthy subjects lactoferrin circulates at concentrations of 2-7 x 10(-6) g/ml. Lactoferrin is a pleiotropic factor with potent antimicrobial and immunomodulatory activities. Recently, we have shown that lactoferrin can also promote bone growth. At physiological concentrations, lactoferrin potently stimulates the proliferation and differentiation of primary osteoblasts and also acts as a survival factor inhibiting apoptosis induced by serum withdrawal. Lactoferrin also affects osteoclast formation and, in murine bone marrow culture, lactoferrin potently inhibits osteoclastogenesis. In vivo, local injection of lactoferrin above the hemicalvaria of adult mice results in substantial increases in the dynamic histomorphometric indices of bone formation and bone area. The mitogenic effect of lactoferrin in osteoblast-like cells is mediated mainly through LRP1, a member of the family of low-density lipoprotein receptor-related proteins that are primarily known as endocytic receptors. Using confocal laser scanning microscopy, we demonstrated that fluorescently labeled lactoferrin is endocytosed and can be visualized in the cytoplasm of primary osteoblastic cells. Lactoferrin also induces activation of p42/44 MAPK signaling in primary osteoblasts, but the two pathways seem to operate independently as activation of MAPK signaling, but not endocytosis, is necessary for the mitogenic effect of lactoferrin. We conclude that lactoferrin may have a physiological role in bone growth and healing, and a potential therapeutic role as an anabolic factor in osteoporosis.     

转化生长因子-β、碱性成纤维生长因子和血小板衍生生长因子在骨折愈合中的表达

目的:观察转化生长因子-β(TGF-β)、碱性成纤维细胞生长因子(bFGF)和血小板衍生生长因子(PDGF)在骨折愈合中的表达和分布情况,进而探讨其作用机制。方法:选用SD大鼠制作胫骨骨折愈合模型,伤后不同时期处死取材,分别进行组织学和TGF-β、bFGF和PDGF免疫组化染色观察。结果:(1)伤后3d开始形成原始骨痂。1周时肉芽组织中的间质细胞开始分化为软骨细胞,软骨形成后再进行软骨内化骨。4周时形成连接骨折端的桥接骨痂。(2)伤后早期血肿中炎性细胞表达bFGF、PDGF。伤后1周骨膜增殖细胞、肉芽组织中的成纤维细胞、内皮细胞、骨端骨细胞以及原始骨痂成骨细胞表达TGF-β、bFGF和PDGF。伤后2周软骨细胞表达TGF-β、bFGF和PDGF。结论:TGF-β、bFGF和PDGF有着各自的表达和分布特点,并共同调解骨原细胞的增殖和成骨细胞、软骨细胞的分化,最终完成骨折愈合。