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Per Borgström

Publications and source records attributed to Per Borgström.

6 recordsLinked to original sources
PubMed2007

Macrophage-mediated bystander effect triggered by tumor cell apoptosis.

Restoration of apoptosis is an important therapeutic strategy for cancer, but bystander effects may be crucial to treatment success. We examined the involvement of bystander effects in the outcome of pro-apoptotic treatments and investigated the role of macrophages. Using a murine N202 breast cancer chamber model and intravital microscopy, we observed bystander apoptosis in vivo in mixed spheroids consisting of bystander N202 cells plus modified N202 cells overexpressing the p14ARF N-terminal region, which promotes p53-mediated apoptosis. The effect was not observed in cocultures in vitro, and could not be transferred through conditioned medium from modified N202 cells. However, if macrophages were also included in the N202 co-cultures, bystander apoptosis was restored, and correlated with elevated surface expression of phosphatidyl serine, a macrophage recognition molecule, on the modified N202 cells. Bystander killing was not observed in cocultures of N202 cells plus macrophages plus cisplatin-treated or 5-fluorouracil-treated N202 cells, where apoptosis induction in the target cell population was inefficient, suggesting that specific activation of macrophages by apoptotic tumor cells was required. The results suggest that pro-apoptotic therapies benefit both from the intrinsic vulnerability of cancer cells to apoptosis and from an innate immune response that amplifies the therapeutic effect.

Animals↗
PubMed2005

Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice.

Tumor cells express tumor-associated antigens (TAAs), which can serve as targets for the immune system. However, the majority of TAAs are overexpressed products of normal cellular genes; as such, self-tolerance mechanisms have hindered their use for the induction of effective antitumor responses. One such normal self-protein is the growth factor receptor Her-2/neu, which is overexpressed in 25-35% of all mammary carcinomas in humans. In previous studies, we have demonstrated that Her-2/neu mice are functionally tolerant to neu antigens and contain only a low avidity T-cell repertoire to neu antigens. However, this residual low-avidity T-cell repertoire has antitumor activity. In this study, we compared the immune responses of Her-2/neu mice immunized with dendritic cells (DCs) pulsed with soluble neu protein or with apoptotic tumor cells. Analysis of the antitumor response shows that Her-2/neu mice vaccinated with DCs pulsed with Her-2/neu antigens retard tumor growth; however, vaccination with DCs pulsed with apoptotic tumor cells induces a stronger antitumor effect. Administration of multiple immunizations in combination with the costimulatory agonist anti-OX40 or anti-4-1BB MAb significantly enhanced the immune responses in these mice, resulting in complete tumor rejection if the tumor burden was small and substantial tumor reduction with a larger tumor burden. These results have important implications for the design of tumor vaccination strategies, suggesting that the use of vaccines that stimulate a broad immune response in combination with costimulatory molecules as immunomodulators could significantly improve the antitumor immune response in tolerant hosts.

Animals↗
PubMed2005

Novel syngeneic pseudo-orthotopic prostate cancer model: vascular, mitotic and apoptotic responses to castration.

We describe a novel syngeneic "pseudo-orthotopic" in vivo model of prostate cancer progression. Our model uses the dorsal skinfold chamber technique with fluorescence video microscopy and TRAMP-C2 tumor cells. The cells were transfected with a histone H2B-GFP fusion protein, permitting real-time measurement of tumor size, as well as mitotic and apoptotic indices. To generate a "pseudo-orthotopic" milieu, pieces of prostate tissue (10-15 mm2) from donor mice were implanted into the chambers of C57BL/6 mice. The prostate tissue grafted into the chambers retained its native vasculature, as determined by transplantation of prostate tissue from GFP transgenic mice. TRAMP-C2 prostate cancer tumor spheroids (25,000 cells) were implanted in the chamber. Without prostate tissue, TRAMP-C2 prostate tumors were poorly angiogenic, displayed low mitotic and apoptotic indices (0.7 x 10(-4)), and no significant tumor growth could be detected. TRAMP-C2 tumors growing on transplanted prostate tissue in the chamber on the other hand had mitotic indices in the order of 1.6 x 10(-4) and apoptotic indices in the order of 0.8 x 10(-4). Furthermore, tumors with stroma were highly angiogenic, and were fully vascularized within 7-10 days. During a 4-week observation period, the number of tumor cells increased by nearly 300%. We used the model to study the effects of surgical castration. The most profound response was a rapid vascular regression of the tumor vasculature. Castration also increased apoptotic indices within the tumor without significant changes in mitosis. This model may be utilized for the rapid analysis of new therapeutic candidates against prostate cancer.

Adenocarcinoma↗
PubMed2002

Low frequency flowmotion/(vasomotion) during patho-physiological conditions.

The role of low frequency flowmotion in physiological or pathophysiological settings is unclear. We performed various series of experiments in young anesthetized New Zealand white (NZW) rabbits. Many animals exhibited flowmotion during control conditions. However, they very often seemed to be in unstable physiological conditions, and our preset inclusion criteria (as to arterial pressure and blood gases) were frequently not met.Therefore, in a first series, we correlated these systematically with the incidence of flowmotion. Eleven of 35 anesthetized rabbits, subjected to extensive surgery, showed flowmotion with a median frequency of 1.5 cpm and a relative "amplitude" of 32%. Arterial pressure was 10 mmHg lower, bicarbonate, base-excess, and PCO(2) values and relative blood flow were also significantly lower compared to animals not exhibiting flowmotion. In a second series, we tested whether flowmotion could be induced by an isolated metabolic acidosis in animals meeting the inclusion criteria and not showing flowmotion at control. Here, flowmotion was induced in 9/10 cases (p < 0.01) 30 min after the start of an HCl-infusion. In a third study, we related the onset of flowmotion to the pressure/flow autoregulation curve. At locally reduced blood pressure all 23 rabbits exhibited flowmotion (p < 0,00001) in the gastrocnemius and the tenuissimus muscles, with maximum flowmotion at a locally reduced blood pressure of 30 mmHg; the LDF-flux level showing 67% of control flow.These results support the concept that low frequency periodic hemodynamics are a characteristic of pathophysiological conditions like hypoperfusion or acidosis rather than indicating a normal physiological state.

Animals↗
PubMedDate not supplied

The roles of epithelial-mesenchymal interactions and the innate immune response on the tumorigenicity of human prostate carcinoma cell lines grown in immuno-compromised mice.

BACKGROUND: Animal models are crucial to further our understanding of the mechanisms of (progressive) growth of prostatic cancer. MATERIALS AND METHODS: We have developed an intravital microscopic model based on the dorsal skinfold chamber technique in mice, allowing continuous measurements of growth and angiogenesis of small tumor spheroids. A histone H2B-GFP fusion protein has been introduced in our cell lines, allowing evaluation of mitotic and apoptotic indices. This system was used to evaluate the growth and angiogenesis of LnCAP, PC3 and DU145 tumor spheroids. RESULTS: LNCAP spheroids regressed rapidly, with complete tumor cell death within 7 days. PC3 spheroids regressed at a slower rate demonstrating a high apoptotic rate, though considerably lower than LNCAP. DU145 spheroids regressed the slowest, demonstrating considerably lower apoptotic rates and measurable mitotic rates. CONCLUSION: The inability to effectively the innate immune system by encapsulation prevents the survival of small human micro-tumor xenografts. Thus, the complex interactions between tumor cells and TAMs, which are pivotal in tumor biology, are extensively perturbed by "foreign" human tumor cells.

Adenocarcinoma↗