Surgery precipitates a hypercoagulable state and has been shown to increase the development of cancer metastases in animal models, however mechanism(s) responsible for this are largely unknown. We hypothesize that the prometastatic effect of surgery may be secondary to postoperative hypercoagulable state. Surgical stress was induced in mice by partial hepatectomy or nephrectomy, preceded by intravenous injection of CT26-LacZ or B16F10-LacZ cells to establish pulmonary metastases with or without perioperative anticoagulation and their lung tumor cell emboli (TCE) were quantified. Fibrinogen and platelets were fluorescently labeled prior to surgical stress to evaluate TCE-associated fibrin and platelet clots. Surgery significantly increased metastases while anticoagulation with five different agents attenuated this effect. Fibrin and platelet clots were associated with TCE significantly more frequently in surgically stressed mice. Surgery promotes the formation of fibrin and platelet clots around TCE and this appears to be the mechanism for the increase in metastases seen following surgery.

Metastases to bone are observed in around 80% of prostate cancer patients and represent the most critical complication of advanced prostate cancer. Unlike other solid tumors that are associated with osteolytic bone metastases, prostate cancer bone metastases stimulate osteoblastic activity with sclerosis in the bone lesions as a consequence. Osteoprotegerin (OPG) is part of a system with three proteins that play a key role in bone remodeling; namely OPG, RANK and RANKL. RANKL regulates osteoclast activity by binding to RANK on the osteoclasts surface, and this interaction is interrupted by OPG. OPG also plays a role in the lifecycle of tumor cells by blocking TNF-related apoptosis-inducing ligand (TRAIL) making it possible for them to evade cell death. The aim of this thesis was to investigate the interaction between the OPG/RANK/RANKL system and prostate cancer. Data showed that there was production of OPG from prostate cancer cell lines in vitro. This expression was under the influence of cytokines that are present in the microenvironment of bone. Further, there was documented a previously unnoticed cell surface expression of RANKL. Co-culturing the prostate cancer with human osteoblasts increased the expression of RANKL. To connect these findings with in vivo studies, OPG-gene single nucleotide polymorphisms (SNP) were investigated. To evaluate OPG SNPs association with bone, a cohort of elderly men was used. OPG SNPs was shown to be correlated to bone mineral density at hip and spine. There was also an association to fragility fractures. Then there was examined the association of the same SNPs to the incidence of prostate cancer but after a four-year follow-up there was no association to the genetic variants. To summarize this research, we hereby present data that the OPG/RANK/RANKL system might be relevant for prostate cancer growth in bone, and for the skeletal related morbidity in this disease. Future in vitro and in vivo studies will demonstrate the relative importance of this crosstalk, and whether pharmacological interference with the system might be used as a therapeutic tool aiming to decrease skeletal morbidity and possibly also prolong survival in prostate cancer.

Les métastases osseuses représentent un enjeu majeur de santé publique en raison de leur impact négatif sur la qualité de vie des patients mais également en raison de l’absence de traitements curatif. De nouvelles pistes thérapeutiques sont explorées dont l’immunothérapie anti-cancéreuse. En tant que principales responsables du recrutement leucocytaire, les chimiokines représentent des outils potentiels dans cette approche thérapeutique. La chimiokine fractalkine (CX3CL1) est impliquée dans de nombreux mécanismes physiologiques et pathologiques, dont le métabolisme osseux, la réponse immunitaire anti-tumorale mais également l’adressage et le développement tumoral, et ce de manière différentielle selon la forme considérée de cette chimiokine. En effet, CX3CL1 a la particularité d’exister sous deux formes : membranaire atypique (propriétés d’adhésion cellulaire) et soluble, typique des chimiokines (propriétés de chimioattraction). La mise en place d’un modèle syngénique murin de métastases osseuses expérimentales de carcinome pulmonaire nous a permis d’étudier l’effet de la forme soluble de CX3CL1 sur le développement métastatique en site osseux. L’expression ectopique de CX3CL1 soluble dans les cellules tumorales pulmonaires a conduit à une diminution de leur potentiel tumorigénique, une diminution de la résorption osseuse associée à une modification du ratio OPG/RANKL en faveur d’un phénotype ostéoblastique et à une modification du recrutement leucocytaire intratumoral en faveur d’une réponse immunitaire anti-tumorale. Outre l’importance de CX3CL1 dans le remodelage osseux, ce travail souligne le rôle essentiel du microenvironnement immunitaire dans la progression tumorale. Dans ce contexte, la forme soluble de CX3CL1 pourrait représenter un outil prometteur dans l’arsenal thérapeutique des métastases osseuses / Bone metastases represent a major public health issue due to their negative impact on patient’s quality of life as well as the current lack of curative treatment. New therapeutic leads are being investigated, among which is the anti-cancer immunotherapy. As the main molecules responsible for leukocyte recruitment, chemokines appear as potential tools for this therapeutic approach. The chemokine fractalkine (CX3CL1) is implicated in numerous physiological and pathological mechanisms, including bone metabolism, antitumor immune response as well as tumor homing and proliferation, in a differential manner depending on the considered form of CX3CL1. Indeed, the particularity of CX3CL1 is that it can exist under two forms: an atypical membrane-bound form (strong cellular adhesion) and a chemokine typical soluble form (chemoattraction). The development of a mouse syngeneic model of lung cancer experimental bone metastases allowed us to study the effect of the soluble CX3CL1 on metastatic development in a skeletal location. The ectopic expression of soluble CX3CL1 in the lung cancer cells led to a decrease of their tumorigenic potential, a decrease of bone resorption associated with a shift of the OPG/RANKL ratio toward an osteoblastic phenotype and a modification of leukocyte tumor infiltration in favor of an antitumor immune response. In addition to the importance of CX3CL1 in bone remodeling, this study underlines the essential role of the immune microenvironment in bone tumor progression. In this context, the soluble CX3CL1 could represent a promising tool in the therapeutic arsenal of bone metastases.

Surgery precipitates a hypercoagulable state and has been shown to increase the development of cancer metastases in animal models, however mechanism(s) responsible for this are largely unknown. We hypothesize that the prometastatic effect of surgery may be secondary to postoperative hypercoagulable state. Surgical stress was induced in mice by partial hepatectomy or nephrectomy, preceded by intravenous injection of CT26-LacZ or B16F10-LacZ cells to establish pulmonary metastases with or without perioperative anticoagulation and their lung tumor cell emboli (TCE) were quantified. Fibrinogen and platelets were fluorescently labeled prior to surgical stress to evaluate TCE-associated fibrin and platelet clots. Surgery significantly increased metastases while anticoagulation with five different agents attenuated this effect. Fibrin and platelet clots were associated with TCE significantly more frequently in surgically stressed mice. Surgery promotes the formation of fibrin and platelet clots around TCE and this appears to be the mechanism for the increase in metastases seen following surgery.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21997号 / 医博第4511号 / 新制||医||1037(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 妹尾 浩, 教授 伊達 洋至 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23074号 / 医博第4701号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 増永 慎一郎, 教授 川口 義弥 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

Basal cell carcinoma is an indolent, slow-growing tumor that rarely metastasizes. Approximately 70% of tumors occur in the head and neck regions. If a basal cell tumor metastasizes, it usually spreads to the regional lymph nodes first, followed by the lungs. We describe a patient with basal cell carcinoma of the right lower extremity with skin metastases. Skin biopsy of one tumor revealed fibroepithelioma of Pinkus, a rare variant of basal cell carcinoma.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12889号 / 論医博第2089号 / 新制||医||1007(附属図書館) / 31643 / (主査)教授 福山 秀直, 教授 千葉 勉, 教授 平岡 眞寛 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

In dogs with large primary tumors, regional lymph node involvement or evidence of distant metastasis can have worse prognoses and significantly decreased survival. Lymph node size alone has been shown to be insufficient as a predictor for the accurate clinical staging of some canine neoplasia, including oral malignant melanoma. However, regional lymph nodes of the oral cavity, such as the medial retropharyngeal lymph nodes, are difficult to access for routine sampling. Diffusion weighted magnetic resonance imaging (DWI) has demonstrated the ability to differentiate metastatic from inflammatory/benign lymph nodes in clinical studies with human cancer patients through the calculation of quantitative values of diffusion termed apparent diffusion coefficients (ADC). The objective of this exploratory study was to evaluate DWI and ADC as potential future methods for detecting malignant lymph nodes in dogs with naturally occurring disease. We hypothesized that DWI would identify significantly different ADC values between benign and metastatic lymph nodes in a group of canine patients with head or neck disease. Our results demonstrated that two of four observers identified a significant difference between the mean ADC values of the benign and metastatic lymph nodes. When data from all four observers were pooled, the difference between the mean ADC values of the benign and metastatic lymph nodes approached but did not reach significance (P-value: 0.0566). Therefore, our hypothesis was not supported. However, DWI does show promise in its ability to differentiate benign from metastatic lymph nodes, and further studies with increased patient numbers are warranted / Master of Science

Conclusion: Surgery should be considered whenever possible. This means that the patient has to be in good clinical condition (Karnofsky performance score > 70), the extracerebral metastases should be stable, the number of cerebral lesions should not exceed more than 3 seedings, and the age of the patient should be below 70 years. Since brain metastases are usually well circumscribed, complete extirpation seems to be possible. Postoperative MRI should be demanded in order to confirm complete extirpation. Additional radiotherapy is indicated in case of subtotal resection of a single lesion and in multiple lesions. In single brain metastasis a prospective randomized trial is necessary to prove whether conventional radiotherapy is essential after surgery in the primary treatment of the tumors or can be delayed until cerebral lesions recur. Radiosurgery is an alternative to surgery in the treatment of metastasis. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.