Idiotype matching: correlation of expression of protective idiotype in sera with survival of tumor mice

A monoclonal anti-Id, 2F10, has previously been shown to protect against transfer of L1210/GZL tumor cells in DBA/2 mice and also to have therapeutic effects in mice with growing tumor. In this study we have measured expression of an idiotope which reacts with a tumor-protective anti-idiotypic antibody, 2F10, in the sera of mice bearing the L1210/GZL tumor. The levels of antibodies binding to 2F10, referred to as the "2F10 idiotope," are different in individual mice and also fluctuate over time. A statistical analysis demonstrated a significant correlation between these changes in 2F10 levels in mice with tumors and their survival times. Increasing 2F10 idiotope in sera of tumor mice correlated with long-term survival, whereas a decreasing trend was found in mice which died shortly after tumor transfer. Correlations between the 2F10 idiotope and survival were observed in groups of mice which had received surgery, cyclophosphamide, a combination of cyclophosphamide and anti-idiotype, or no treatment at all. No correlation between a nonrelated idiotope and survival was noted. Although 2F10 is an idiotope expressed by an anti-tumor-associated Ag antibody, the correlation between anti-tumor-associated Ag titers and survival was significantly lower than that between the 2F10 idiotope and survival. This demonstrates that 2F10 is preferentially associated with antibodies which are involved in tumor regression. Thus, the 2F10 idiotope in sera of tumor-bearing mice has predictive value for survival and tumor regression.     

Mean nuclear area of fine needle aspirates of primary preoperative palpable breast carcinoma using image cytometry

OBJECTIVE: Early, operable breast cancers in appropriate patients are increasingly being treated preoperatively using neoadjuvant chemotherapy. A good response rate is seen with high grade tumors. Nuclear size, which may reflect the grade of the tumor, is also of possible prognostic value in breast cancer. STUDY DESIGN: We measured the mean nuclear area (MNA) of 114 consecutive preoperative fine needle aspirates of palpable, operable breast cancers. We used computerized image cytometry to measure nuclear area to determine tumor biology and possible grade prior to treatment. RESULTS: Histologic grade distribution was as follows: low grade, 15%; moderate grade, 40%; and high grade, 45%. Mann-Whitney test for trend on tumor size and histologic grade between MNA showed a significant relationship between MNA and tumor size (P=.016) but no significance between MNA and histologic grade (P =.22). The chi2 and Fisher Exact Test between MNA and node-positive or -negative patients showed no significance. CONCLUSION: When correlating MNA with tumor size and histologic grade, high MNA is present at a higher frequency as tumor size and histologic grade increase.     

p53在诱导性多潜能干细胞向肿瘤细胞转化中的作用

p53基因是抑制肿瘤形成的抑癌基因,p53通过阻断细胞周期、诱导衰老细胞凋亡和修复受损的DNA从而抑制肿瘤的形成。而突变的p53则具有相反的功能,被认为是促进细胞重编程的关键。这些发现表明p53在去分化过程中具有重要的作用,而肿瘤的形成与细胞重编程存在高度的相似性,所以探讨p53与诱导性多能干细胞(induced pluripotent stem cell,iPSC)和肿瘤形成之间的联系具有一定的意义。     

Proteases as modulators of tumor-stromal interaction: primary tumors to bone metastases

As cells undergo oncogenic transformation and as malignant cells arrive at metastatic sites, a complex interplay occurs with the surrounding stroma. This dialogue between the tumor and stroma ultimately dictates the success of the tumor cells in the given microenvironment. As a result, understanding the molecular mechanisms at work is important for developing new therapeutic modalities. Proteases are major players in the interaction between tumor and stroma. This review will focus on the role of proteases in modulating tumor-stromal interactions of both primary breast and prostate tumors as well as at bone metastatic sites in a way that favors tumor growth.     

A Biased Competition Theory of Cytotoxic T Lymphocyte Interaction with Tumor Nodules

The dynamics of the interaction between Cytotoxic T Lymphocytes (CTL) and tumor cells has been addressed in depth, in particular using numerical simulations. However, stochastic mathematical models that take into account the competitive interaction between CTL and tumors undergoing immunoediting, a process of tumor cell escape from immunesurveillance, are presently missing. Here, we introduce a stochastic dynamical particle interaction model based on experimentally measured parameters that allows to describe CTL function during immunoediting. The model describes the competitive interaction between CTL and melanoma cell nodules and allows temporal and two-dimensional spatial progression. The model is designed to provide probabilistic estimates of tumor eradication through numerical simulations in which tunable parameters influencing CTL efficacy against a tumor nodule undergoing immunoediting are tested. Our model shows that the rate of CTL/tumor nodule productive collisions during the initial time of interaction determines the success of CTL in tumor eradication. It allows efficient cytotoxic function before the tumor cells acquire a substantial resistance to CTL attack, due to mutations stochastically occurring during cell division. Interestingly, a bias in CTL motility inducing a progressive attraction towards a few scout CTL, which have detected the nodule enhances early productive collisions and tumor eradication. Taken together, our results are compatible with a biased competition theory of CTL function in which CTL efficacy against a tumor nodule undergoing immunoediting is strongly dependent on guidance of CTL trajectories by scout siblings. They highlight unprecedented aspects of immune cell behavior that might inspire new CTL-based therapeutic strategies against tumors.     

Mechanistic characterization of oscillatory patterns in unperturbed tumor growth dynamics: The interplay between cancer cells and components of tumor microenvironment

Mathematical modeling of unperturbed and perturbed tumor growth dynamics (TGD) in preclinical experiments provides an opportunity to establish translational frameworks. The most commonly used unperturbed tumor growth models (i.e. linear, exponential, Gompertz and Simeoni) describe a monotonic increase and although they capture the mean trend of the data reasonably well, systematic model misspecifications can be identified. This represents an opportunity to investigate possible underlying mechanisms controlling tumor growth dynamics through a mathematical framework. The overall goal of this work is to develop a data-driven semi-mechanistic model describing non-monotonic tumor growth in untreated mice. For this purpose, longitudinal tumor volume profiles from different tumor types and cell lines were pooled together and analyzed using the population approach. After characterizing the oscillatory patterns (oscillator half-periods between 8–11 days) and confirming that they were systematically observed across the different preclinical experiments available (p<10^?9), a tumor growth model was built including the interplay between resources (i.e. oxygen or nutrients), angiogenesis and cancer cells. The new structure, in addition to improving the model diagnostic compared to the previously used tumor growth models (i.e. AIC reduction of 71.48 and absence of autocorrelation in the residuals (p>0.05)), allows the evaluation of the different oncologic treatments in a mechanistic way. Drug effects can potentially, be included in relevant processes taking place during tumor growth. In brief, the new model, in addition to describing non-monotonic tumor growth and the interaction between biological factors of the tumor microenvironment, can be used to explore different drug scenarios in monotherapy or combination during preclinical drug development.     

Interactions of tumor cells with dendritic cells: balancing immunity and tolerance

Dendritic cells (DCs) are antigen-presenting cells specialized to initiate and maintain immunity and tolerance. DCs initiate immune responses in a manner that depends on signals they receive from pathogens, surrounding cells and their products. Most tumors are infiltrated by DCs. Thus, interactions between DCs and dying tumor cells may determine the balance between immunity and tolerance to tumor cells. In addition, DCs also display non-immunologic effects on tumors and the tumor microenvironment. Therefore, improved understanding of the cross talk between tumor cells and DCs may suggest new approaches to improve cancer therapy.     

Release of neuropeptide Y and hemodynamic changes during surgical removal of human pheochromocytomas

This study investigates the release of Neuropeptide Y from eight human pheochromocytomas. Profil immunoreactive Neuropeptide Y (Ir-NPY) levels during the management of surgery were compared with these of norepinephrine (NE) while hemodynamics were monitored. Plasma IrNPY and NE levels increased during tumor manipulation and returned to near normal one hour after operation. However, Ir-NPY levels remained high just after tumor resection while NE levels were significantly decreased. At tumor manipulation and just after tumor resection, plasma Ir-NPY levels were correlated with the systemic vascular resistances (SVR) (r = 0.74; P<0.04 and r = 0.86; P<0.006 respectively). No correlation was found either between plasma Ir-NPY and NE levels or between plasma NE levels and SVR. The release of Ir-NPY from tumor tissue, studied by a superfusion method, exhibited a significant correlation with the plasma Ir-NPY concentrations at the time of corresponding tumor resection (r = 0.95; P<0.007). Chromatographic analysis showed that Ir-NPY in plasma and outflow migrate as human NPY (1-36). These results confirmed that in pheochromocytoma, plasma NPY mainly originates from the tumor and argue for an important role of NPY in pheochromocytoma hypertension as indicated by the correlation between the Ir-NPY levels and the SVR.     

联合检测E-cadherin, VEGF表达水平在卵巢良恶性肿瘤诊断中的临床价值

目的:探讨联合检测E-钙粘素(E-cadherin)、血管内皮生长因子(VEGF)表达水平在卵巢良恶性肿瘤诊断中的临床价值。方法:收取2012年1月至2016年1月间我院收治的卵巢良恶性肿瘤患者共83例,使用免疫组化方法检测对E-cadherin及VEGF表达情况进行分析与比较。结果:E-cadherin在卵巢良性肿瘤、卵巢交界性肿瘤及卵巢恶性肿瘤中的阳性表达率分别为64.71%、44.44%及25.00%,VEGF在卵巢良性肿瘤、卵巢交界性肿瘤及卵巢恶性肿瘤中的阳性表达率分别为11.76%、33.33%及83.33%,上述差异均具有统计学意义(P0.05)。E-cadherin及VEGF在卵巢恶性肿瘤中的表达与分化程度、FIGO分期有关(P0.05)。VEGF表达与淋巴结转移有关(P0.05),但E-cadherin与淋巴结转移关系不大(P0.05)。E-cadherin及VEGF表达呈负相关(r=-0.472,P0.05)。结论:E-cadherin低表达及VEGF高表达与卵巢恶性肿瘤发生、发展及侵袭有密切关系。     

Notch signaling in the regulation of tumor angiogenesis

The Notch signaling pathway is conserved in vertebrates and invertebrates and is involved in many developmental processes. Notch receptors and ligands are expressed on the cell surface enabling interactions between adjacent cells upon receptor-ligand binding. Notch signaling molecules have an important well-documented role in vascular development, differentiation, proliferation, apoptosis and tumorigenesis. Recently, several groups have identified the importance of Notch signaling in tumor angiogenesis. Notch activity increases specifically in tumor endothelium and in various tumors types and, in some studies, Notch signaling suppresses angiogenic processes. Because the Notch signaling pathway can mediate communication between various cell types in the tumor microenvironment, interactions between tumor cells and endothelial cells might promote angiogenesis, therefore targeting the Notch pathway might provide a novel strategy for anti-angiogenic therapies. Here, we discuss recent insights of Notch signaling in tumor angiogenesis.     

Interchange of amino acids between tumor and host.

During the growth of a tumor, there are very relevant changes in the metabolism of the host to produce the metabolites rapidly consumed by the tumor. In this context, the exchanges of amino acids between the tumor and its host are especially important; however, they have received little attention. A rigorous study must provide data on the growth curve of the tumor, as well as on amino acid levels in tumor cells, plasma, and metabolically relevant tissues and organs from the host during the whole growth of the tumor. The main conclusions arising from a complete study in a tumor model are discussed.     

A novel method of protein analysis for prediction of biological function: application to tumor toxins

Informational spectra method was applied to the analysis of lymphotoxin and tumor necrosis factor. The correlation between the information contained in primary structure of these tumor toxins and some oncogen transforming proteins was established. This correlation implies the possibility of a competitive action between these two groups of proteins. "Hot spots" positions in the primary structure of lymphotoxin and tumor necrosis factor for the functional "up" and "down" mutations were predicted.     

Collective dynamics of cancer cells confined in a confluent monolayer of normal cells

Tumorigenesis often involves specific changes in cell motility and intercellular adhesion. Understanding the collective cancer cell behavior associated with these specific changes could facilitate the detection of malignant characteristics during tumor growth and invasion. In this study, a cellular vertex model is developed to investigate the collective dynamics of a disk-like aggregate of cancer cells confined in a confluent monolayer of normal cells. The effects of intercellular adhesion and cell motility on tumor progression are examined. It is found that the stresses in both the cancer cells and the normal cells increase with tumor growth, resulting in a crowded environment and enhanced cell apoptosis. The intercellular adhesion between cancer cells and normal cells is revealed to promote tumor growth and invasion. The tumor invasion dynamics hinges on the motility of cancer cells. The cancer cells could orchestrate into different collective migration modes, e.g., directional migration and rotational oscillations, dictated by the competition between cell persistence and local coordination. Phase diagrams are established to reveal the competitive mechanisms. This work highlights the role of mechanics in regulating tumor growth and invasion.     

In situ lymphoid cells of mouse mammary tumors. IV. Comparison of functional activity of lymphoid cells separated from mammary tumors to that of spleen and lymph node cells of tumor-sensitized mice.

Lymphoid cells isolated form several types of mouse mammary tumors are capable of stimulating tumor cell growth or survival in MCT assays. Lymph node and spleen cells of mice bearing such a tumor are specifically cytotoxic to the tumor cells. Surgical removal of the tumor is followed in 4 to 7 days by the appearance of stimulatory capacity in spleens and lymph nodes. By day 10, cytotoxic cells specific for the sensitizing tumor are again detected. These reach a peak on day 13. By day 17 no reactivity is detectable. The functional distribution of tumor-reactive lymphoid cells is different between tumor masses and peripheral lymphoid organs.     

A cellular automata model of tumor-immune system interactions

We present a hybrid cellular automata-partial differential equation model of moderate complexity to describe the interactions between a growing tumor next to a nutrient source and the immune system of the host organism. The model allows both temporal and two-dimensional spatial evolution of the system under investigation and is comprised of biological cell metabolism rules derived from both the experimental and mathematical modeling literature. We present numerical simulations that display behaviors which are qualitatively similar to those exhibited in tumor-immune system interaction experiments. These include spherical tumor growth, stable and unstable oscillatory tumor growth, satellitosis and tumor infiltration by immune cells. Finally, the relationship between these different growth regimes and key system parameters is discussed.     

Modeling age-specific incidence of colon cancer via niche competition

Cancer development is a multistep process often starting with a single cell in which a number of epigenetic and genetic alterations have accumulated thus transforming it into a tumor cell. The progeny of such a single benign tumor cell expands in the tissue and can at some point progress to malignant tumor cells until a detectable tumor is formed. The dynamics from the early phase of a single cell to a detectable tumor with billions of tumor cells are complex and still not fully resolved, not even for the well-known prototype of multistage carcinogenesis, the adenoma-adenocarcinoma sequence of colorectal cancer. Mathematical models of such carcinogenesis are frequently tested and calibrated based on reported age-specific incidence rates of cancer, but they usually require calibration of four or more parameters due to the wide range of processes these models aim to reflect. We present a cell-based model, which focuses on the competition between wild-type and tumor cells in colonic crypts, with which we are able reproduce epidemiological incidence rates of colon cancer. Additionally, the fraction of cancerous tumors with precancerous lesions predicted by the model agree with clinical estimates. The correspondence between model and reported data suggests that the fate of tumor development is majorly determined by the early phase of tumor growth and progression long before a tumor becomes detectable. Due to the focus on the early phase of tumor development, the model has only a single fit parameter, the time scale set by an effective replacement rate of stem cells in the crypt. We find this effective rate to be considerable smaller than the actual replacement rate, which implies that the time scale is limited by the processes succeeding clonal conversion of crypts.     

Synthesis and antitumor activity of CBI-bearing ester and carbamate prodrugs of CC-1065 analogue

Prodrugs of a CBI-bearing CC-1065 analogue were synthesized. Antitumor activity of the compounds was evaluated against tumor cells in vitro and in mouse tumor models. Compounds 1 and 7, bearing methylpiperazine and DHA moieties, respectively, showed significant antitumor activity in both the L1210 leukemia and Lewis lung carcinoma mouse tumor models. For the carbamate prodrugs 1-4 and 6, there is a good correlation between the drug's potency both in vitro and in animal tumor models; however, there is no correlation between the prodrug's antitumor activity and the type of bonds linking the free drug. There are no significant differences between the antitumor activities of those that can or cannot be protonated at physiological pH. Compounds 6 and 7, each bearing a DHA moiety, did not show significantly improved antitumor activity compared to other prodrugs bearing DHA moieties, suggesting that DHA may not be used universally to significantly improve a drug's antitumor efficacy.