Treatment Of Lymphatic Metastasis Research Articles

Combined Doxorubicin Mesoporous Carbon Nanospheres for Effective Tumor Lymphatic Metastasis by Multi-Modal Chemo-Photothermal Treatment in vivo.

Sentinel lymph node (SLN) is the first regional lymph node where tumor cells metastasize, and its identification and treatment are of great significance for the prevention of tumor metastasis. However, the current clinical modalities for identification and treatment of SLN are still far from satisfactory owing to their high cost, invasiveness and low accuracy. We aim to design a novel nanomedicine system for SLN imaging and treatment with high efficacy. We designed and prepared hollow mesoporous carbon spheres (HMCS) and loaded with the chemotherapeutic drug doxorubicin (DOX), which is then modified with polyvinyl pyrrolidone (PVP) to obtain nanomedicine: HMCS-PVP-DOX. HMCS-PVP with a size of about 150 nm could retain in the lymph nodes for a long time and stain the lymph nodes, which could be easily observed by the naked eye. At the same time, HMCS-PVP exhibited excellent photoacoustic and photothermal imaging capabilities, realizing multimodal imaging to locate lymph nodes precisely. Due to its high specific surface area, HMCS could be largely loaded with the chemotherapeutic drug doxorubicin (DOX). HMCS-PVP-DOX displayed highly efficient synergistic chemotherapy-photothermal therapy for lymphatic metastases in both cellular and animal experiments due to its significant photothermal effect under 1064 nm laser irradiation. HMCS-PVP-DOX also displayed great stability and biosafety. Multifunctional nanomedicine HMCS-PVP-DOX is expected to provide a novel paradigm for designing nanomedicine to the diagnosis and treatment of lymphatic metastases because of its good stability and safety.

Lymphatic metastasis of bladder cancer: Molecular mechanisms, diagnosis and targeted therapy.

Bladder cancer is the most common and lethal cancer of the urinary system. Lymphatic metastasis is the primary and main metastatic type of bladder cancer, leading to an extremely poor prognosis in patients. Therefore, a better understanding of molecular mechanisms may provide potential targets for the diagnosis and treatment of lymphatic metastasis in bladder cancer. Herein, we summarize the current knowledge of molecular mechanisms of the lymphatic metastasis in bladder cancer, including lymphangiogenesis and its regulators, noncoding RNAs, and microenvironment-associated molecules. Novel radiomics and genomics approaches have substantially improved the preoperative diagnostic accuracy of lymph node metastasis in patients with bladder cancer. Newly discovered targets may lead to promising therapeutic strategies for clinical intervention in lymphatic metastasis of bladder cancer. More basic and translational studies need to be conducted to further clarify the molecular mechanisms, and identify predictive markers and therapeutic targets of lymphatic metastasis for bladder cancer patients.

Nanoparticle drug-delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle.

Nanoparticle (NP)-based drug-delivery systems are frequently employed to improve the intravenous administration of chemotherapy; however, few reports explore their application as an intraperitoneal therapy. We developed a pH-responsive expansile nanoparticle (eNP) specifically designed to leverage the intraperitoneal route of administration to treat intraperitoneal malignancies, such as mesothelioma, ovarian, and pancreatic carcinomatoses. This review describes the design, evaluation, and evolution of the eNP technology and, specifically, a Materials-Based Targeting paradigm that is unique among the many active- and passive-targeting strategies currently employed by NP-delivery systems. pH-responsive eNP swelling is responsible for the extended residence at the target tumor site as well as the subsequent improvement in tumoral drug delivery and efficacy observed with paclitaxel-loaded eNPs (PTX-eNPs) compared to the standard clinical formulation of paclitaxel, Taxol®. Superior PTX-eNP efficacy is demonstrated in two different orthotopic models of peritoneal cancer-mesothelioma and ovarian cancer; in a third model-of pancreatic cancer-PTX-eNPs demonstrated comparable efficacy to Taxol with reduced toxicity. Furthermore, the unique structural and responsive characteristics of eNPs enable them to be used in three additional treatment paradigms, including: treatment of lymphatic metastases in breast cancer; use as a highly fluorescent probe to visually guide the resection of peritoneal implants; and, in a two-step delivery paradigm for concentrating separately administered NP and drug at a target site. This case study serves as an important example of using the targeted disease-state's pathophysiology to inform the NP design as well as the method of use of the delivery system. WIREs Nanomed Nanobiotechnol 2017, 9:e1451. doi: 10.1002/wnan.1451 For further resources related to this article, please visit the WIREs website.

Follicle-stimulating hormone polypeptide modified nanoparticle drug delivery system in the treatment of lymphatic metastasis during ovarian carcinoma therapy

ObjectiveTraditional chemotherapy drugs have an obvious drawback of nonspecific biodistribution in treating ovarian cancer. Follicle-stimulating hormone receptor (FSHR), a G-protein coupled receptor which is mainly expressed in reproductive system, is an important drug target in developing novel therapeutics. MethodsUsing a polypeptide of follicle-stimulating hormone (named as FSHP), a conjugated nanoparticle, FSHP-NP was developed to target FSHR in lymphatic metastasis of ovarian cancer. FSHP-NP was tested for recognition specificity and uptake efficiency on FSHR-expressing cells. A paclitaxel (PTX)-loaded FSHP-NP (FSHP-NP-PTX) was further developed and its anti-tumor effect was determined in vivo and in vitro. ResultsTaking NuTu-19 cells as an example, FSHP-NP-PTX displayed significantly stronger anti-cell proliferative and anti-tumor effects in a dose- and time-dependent manner when compared with free PTX or naked PTX-loaded nanoparticles (NP-PTX) in vitro. In vivo examinations showed that the size and weight of the lymph nodes were reduced in the FSHP-NP-PTX group. ConclusionFSHR as a novel therapeutic target in ovarian cancer and delivery of PTX via conjugated nanoparticle (FSHP-NP) might represent a new therapeutic approach in ovarian cancer.

Abstract B79: Postpartum mammary gland involution drives COX-2-dependent lymphangiogenesis and lymphatic vessel invasion in a model of postpartum breast cancer

Abstract Women diagnosed with breast cancer within five years postpartum have worse prognosis than age-matched nulliparous women, independent of tumor stage1,2. While lymph node involvement, lymphatic vessel presence at the tumor margin, and invasion of tumor cells into peritumor lymphatics are all poor prognostic factors for breast cancer patients1-3; it is unknown if lymphatic vessel invasion plays a role in the poor prognosis of postpartum breast cancer. To address this question, we utilized a cohort of young women's breast cancer cases balanced for patient age, tumor stage, and tumor biologic subtype. We observe increased lymph vessel density (LVD) and lymph vessel specific invasion (LSI) in the peritumor region of tumors from postpartum cases compared to nulliparous cases, consistent with a role for lymphatic vessel invasion in postpartum breast cancer metastasis. In addition, we observe increased LVD in normal mammary tissue from postpartum women suggesting that lymphangiogenesis is activated in the postpartum gland. We hypothesize that expansion of the lymphatic vasculature occurs during normal postpartum mammary gland regression, known as postpartum involution, and that tumor cells exposed to the involution microenvironment similarly upregulate lymphangiogenesis, providing increased opportunity for metastasis. To test this hypothesis, we measured LVD in normal rodent mammary tissues and observed a significant increase in LVD during postpartum mammary gland involution. We then utilized our mouse xenograft model of postpartum breast cancer to test whether postpartum tumors have increased LVD and LSI. In this model, postpartum tumors invade the surrounding mammary stroma and peripheral blood, and infiltrate the lung at increased frequency compared to nulliparous tumors4. Here, we also observe increased LVD and LSI in the peritumor region in the postpartum group. Furthermore, we utilized COX-2 inhibitors to show that COX-2 activity during involution is required for the increased LVD, LSI, and lung infiltration associated with postpartum tumors. COX-2 inhibitors also significantly reduced LVD in the normal gland during involution without interfering with morphological gland regression. Finally, tumor cells exposed to postpartum involution appear to be stably altered, as transplantation of postpartum tumor cells into nulliparous mice show elevated levels of tumor associated lymphatics. We conclude that tumor cells exploit the normal lymphangiogenesis programs of postpartum involution to persistently upregulate lymphangiogenesis, which may explain the increased metastasis observed in postpartum tumors. This work was funded by DOD, ACS, Komen, and Cancer League of Colorado.

Effects of aspirin on mesenteric lymph nodes of rabbits as basis for its use on lymph nodes metastases

To evaluate the effects of aspirin 10% and 20% on mesenteric lymph nodes of rabbits as basis for its use on lymph nodes metastases. A total of 20 lymph nodes from 20 rabbits (randomized in four groups) were evaluated. Aspirin solutions 10% (groups A and C) and 20% (groups B and D) were injected into mesenteric lymph nodes of healthy rabbits and had its gross and histological effects evaluated at 24 hours (groups A and B) and at seven days (groups C and D). In the groups A and B evaluated at 24 hours it was observed extensive necrosis and hemorrhage, a significant increase in apoptosis throughout the lymph node with medullary sinuses enlargement and an increase in germinal centers. In the groups C and D evaluated at seven days of solution injection there was also an increase in apoptosis with higher elevation of histiocytes and a significant decrease of necrosis and an increase of giant cells was noticed causing a foreign body chronic inflammation. In all comparisons, there were no differences between the concentrations used (10 and 20%). The injection of aspirin on lymph nodes caused necrosis and an increase of apoptosis after 24 hours and after seven days of treatment there was regeneration of the lymph nodes, with intense decrease of necrosis and a great elevation of apoptosis. These experimental results support future clinical studies on application of aspirin in the treatment of lymphatic metastases, since the increase of apoptosis is one of the pillars of cancer therapy.

Localized doxorubicin chemotherapy with a biopolymeric nanocarrier improves survival and reduces toxicity in xenografts of human breast cancer

Patients with metastatic breast cancer have a five-year survival rate of 27% compared to 98% for localized cancer, and the presence of even a few cancer cells in lymph nodes, known as isolated tumor cells or nanometastases, significantly increases the risk of relapse in the absence of aggressive treatment. Therefore, diagnosis and treatment of lymphatic metastases in early breast cancer plays an important role in patient survival. Here, we demonstrate the first description of a delivery system for localized doxorubicin chemotherapy to the breast tissue. The hyaluronan–doxorubicin nanoconjugate exhibits a sustained release characteristic in vitro and in vivo in the breast tissues of rodents bearing human breast cancer xenografts. In addition, the conjugate reduces dose-limiting cardiac toxicity with minimal toxicity observed in normal tissues. Finally, the conjugate dramatically inhibits breast cancer progression in vivo, leading to an increased survival rate. Thus, localized chemotherapy to the breast lymphatics with a nanocarrier may represent an improved strategy for treatment of early stage breast cancers.

Modulation of Cellular Invasion by VEGF-C Expression in Squamous Cell Carcinoma of the Head and Neck

To determine how vascular endothelial growth factor C (VEGF-C) affects tumor cell invasion and motility in squamous cell carcinoma of the head and neck (SCCHN). A molecular biology study. The VEGF-C coding sequence was cloned into an expression vector and stably transfected into the SCCHN cell line SCC116 to create the SCC116-VEGFC line. RNA interference (RNAi) was used to block VEGF-C expression. An adenoviral system for expressing VEGF-C RNAi was developed and tested. An academic hospital laboratory. Relative VEGF-C RNA levels were determined by real-time quantitative reverse transcriptase-polymerase chain reaction, and protein expression was evaluated by Western blot. Cellular invasion was evaluated by 24-hour semipermeable membrane transit assay. SCC116-VEGFC cells had markedly increased expression of VEGF-C protein and RNA compared with normal SCC116 controls. SCC116-VEGFC cells produced marked increases in cellular invasion and motility compared with SCC116 cells. Blockade of VEGF-C expression by transfection of a VEGF-C RNAi expression plasmid into both SCC116 and SCC116-VEGFC cells induced a 38% decrease in SCCHN invasion and motility as tested by a semipermeable membrane invasion assay. We developed an adenoviral expression system for VEGF-C RNAi, which also induced a dose-dependent decrease in cellular invasion in the highly invasive DM12 cell line. These studies demonstrate that intracellular VEGF-C levels modulate in vitro SCCHN motility and invasion. Further work is needed to clarify the specific receptors and signaling pathways that are involved in SCCHN motility. Molecular therapies that inhibit the VEGF-C pathway may have clinical potential in the treatment of lymphatic metastasis in SCCHN.

Vascular Endothelial Growth Factor-A Promotes Peritumoral Lymphangiogenesis and Lymphatic Metastasis

Metastases are commonly found in the lymphatic system. The molecular mechanism of lymphatic metastasis is, however, poorly understood. Here we report that vascular endothelial growth factor (VEGF)-A stimulated lymphangiogenesis in vivo and that overexpression of VEGF-A in murine T241 fibrosarcomas induced the growth of peritumoral lymphatic vessels, which occasionally penetrated into the tumor tissue. As a result of peritumoral lymphangiogenesis, metastases in lymph nodes of mice were detected. VEGF-A-overexpressing tumors contained high numbers of infiltrating inflammatory cells such as macrophages, which are known to express VEGF receptor (VEGFR)-1. It seemed that in the mouse cornea, VEGF-A stimulated lymphangiogenesis through a VEGF-C/-D/VEGFR-3-independent pathway as a VEGFR-3 antagonist selectively inhibited VEGF-C-induced, but not VEGF-A-induced, lymphangiogenesis. Our data show that VEGF-A contributes to lymphatic mestastasis. Thus, blockage of VEGF-A-induced lymphangiogenesis may provide a novel approach for prevention and treatment of lymphatic metastasis.

PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis

Cancer metastases are commonly found in the lymphatic system. Like tumor blood angiogenesis, stimulation of tumor lymphangiogenesis may require the interplay of several tumor-derived growth factors. Here we report that members of the PDGF family act as lymphangiogenic factors. In vitro, PDGF-BB stimulated MAP kinase activity and cell motility of isolated lymphatic endothelial cells. In vivo, PDGF-BB potently induced growth of lymphatic vessels. Expression of PDGF-BB in murine fibrosarcoma cells induced tumor lymphangiogenesis, leading to enhanced metastasis in lymph nodes. These data demonstrate that PDGF-BB is an important growth factor contributing to lymphatic metastasis. Thus, blockage of PDGF-induced lymphangiogenesis may provide a novel approach for prevention and treatment of lymphatic metastasis.

Controversies in the management of metastatic melanoma to regional lymphatic basins.

The primary management of lymph nodes involved with metastatic melanoma is regional lymphadenectomy. Many controversies of regional lymph node dissection exist including extent and nature of the lymphadenectomy, treatment of lymphatic metastases in unusual locations and the role of adjuvant radiotherapy. Although radical neck dissection has been the gold standard for cervical disease, modified dissections do not seem to compromise regional control in appropriately selected patients. In the axilla, a Level I, II, and III dissection is most commonly performed. Combined superficial and deep groin dissection is justified for clinically palpable disease although management of patients with histologically positive yet clinically non-palpable disease is more controversial. Burden of disease, imaging, patient co-morbidity, and Cloquet nodal status must be considered. Many technical variations exist in an attempt to improve morbidity rates secondary to lymphadenectomy. Unfortunately, complication rates are difficult to compare secondary to variable study designs, definitions, and patient populations. Adjuvant radiation therapy appears warranted in patients with high risk of regional recurrence including bulky disease, extracapsular extension or cervical location.

睾丸絨毛癌の治療成績

The purpose of the present paper is to briefly document the diagnosis and treatment of choriocarcinoma of the testis in cases seen at the Yokosuka National Hospital, Cancer Institute Hospital and Yokohama City University Hospital.1. A total of 149 cases of testicular tumor were seen at these medical institutions during the period from January, 1962 to December, 1972. Of these 149, 10 (6.7%) were of choriocarcinoma.2. The histological diagnosis of the malignancy in this series of 10 cases was made in various ways. In only 4 of these 10, ordinary histological examination of primary lesion revealed choriocarcinoma. In another 2 cases, definite diagnostic evidence was obtained by examination of serial sections of primary tumor. In the remaining 4 cases, routine histology of primary tumor failed to provide conclusive evidence of malignancy and the diagnosis was established only by biopsy of lymphatic metastases in 2 of them and by autopsy in the other 2.3. Urinary HCG was found to be well correlated with neoplastic activity.4. Gynecomastia was seen in 4 of the 10 cases.5. In all cases but one, the patients died of malignancy, the prognosis of choriocarcinoma of the testis being thus very poor. The time period from the first examination to patient's death in these 9 cases ranged from 19 days to 2 years, averaging 10.6 months.6. All the patients who died had extensive pulmonary metastasis.7. Autopsy was performed in 6 of the 9 cases. As for organ metastasis, pulmonary metastasis was present invariably in all cases, hepatic metastasis in 5 cases, and the brain, kidneys and pancreas were involved in 2 cases each. With regard to lymphatic metastasis, retroperitoneal lymph nodes were found affected in one case; retroperitoneal lymph nodes and supraclavicular lymph nodes were concurrently involved in 2 cases. In the latter 3 cases, metastasis occurred probably through lymphatic channels.8. In the chemotherapy of choriocarcinoma of the testis, an intermittent multidrug regimen proved to be effective. Our recommended chemotherapeutic regimen for Japanese patients is as follows: actinomycin D, 0.5mg per day, methotrexate, 5mg per day, and cyclophosphamide, 250mg per day, given in 5-day courses. Initial 4 to 5 courses of treatment are given at 2 to 3-week intervals and then, after an interval of 2 to 3 months, the treatment is repeated in the same way over an entire period of 2 years unless significant side effects occur.Under this therapeutic regimen, serum LDH and urinary HCG returned to normal in one case. Another patient with stage I choriocarcinoma of the testis has now survived 4 years following orchiectomy which was done after 2 years of this particular chemotherapy.9. Irradiation, which heretofore is considered useless, proved to be fairly effective in the treatment of lymphatic metastasis; gratifying results were obtained in one case with metastasis to retroperitoneal lymph nodes and in 4 with metastatic lesions of supraclavicular lymph nodes.