The delivery of therapeutic drugs to solid tumours may be impaired by structural and functional abnormalities in blood and lymphatic vessels. Here we provide evidence that proliferating cancer cells ...cause intratumour vessels to compress and collapse. By reducing this compressive mechanical force and opening vessels, cytotoxic cancer treatments have the potential to increase blood perfusion, thereby improving drug delivery.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2003.
Includes bibliographical references (leaves 146-166).
Lymph node metastases have a negative impact on cancer survival, ...but the mechanisms for lymphatic metastasis are not well understood. The universal finding in solid tumors of an absence of functional lymphatic vessels seems paradoxical, as cancer cells do travel through lymphatics in order to disseminate. In order to address some of these issues, this thesis proposes two etiologies for the absence of functional lymphatic vessels in solid tumors. The first hypothesis addresses whether Vascular Endothelial Growth Factor-C (VEGF-C), a lymphangiogenic factor, was sufficient to induce lymphatic function in tumors. The overexpression of VEGF-C in tumors leads to an increase in lymph node metastasis as well as structures that positively stain for lymphatic markers, but does not induce functional lymphatics within the tumor. Thus VEGF-C is not sufficient to grow functional lymphatic vessels in tumors. The second hypothesis addresses whether mechanical forces generated by the proliferation of cancer cells in a confined space compress lymphatic vessels in tumors. The mechanical forces inside of the tumor were reduced by the selective killing of human cancer cells grown in mice by Diphtheria Toxin. Tumor cell death leads to an increase in the fraction of lymphatics with open lumen. In addition, lymphatic vessels with open lumen are surrounded by a lower cellular density than collapsed vessels. Thus, relieving solid stress allows lymphatic vessels to open. However, function was not restored in these vessels. This is presumably due to the inability of the lymphatic vessels to completely open along its entire length, leaving focal areas of lymphatic collapse. Compressive forces are common to all growing tumors, giving credence to the mechanical etiology of the absence of functional lymphatic vessels in tumors, regardless of tumor type or organ site.
(cont.) These findings lead to an interesting question: Does cancer treatment in humans relieve the mechanical compression allowing lymphatic and blood vessels to open? Furthermore, would the resumption of function of compressed blood and lymphatic vessels lead to a paradoxical increase in metastasis? These questions require further investigation.
by Timothy P. Padera.
Ph.D.
A 17-year-old male presented with pain in his lower-left chest. He had no significant medical history and was previously in good health. He had a fractured ninth left anterior rib and the tenth, ...eleventh and twelfth ribs were absent, which was thought to be a congenital anomaly. Several months later, he presented again with back pain, an enlarging mass in the lower-left chest wall, erosion of the lateral pedicles of the lower thoracic vertebrae and pleural effusion.
Physical examination, chest X-ray, MRI of the spine, incisional biopsy, serial CT imaging of the hemithorax, immunohistochemistry, flow cytometry, and enzyme-linked immunosorbent assays.
Gorham's lymphangiomatosis with expression of platelet-derived growth factor receptor-beta and elevated circulating platelet-derived growth factor-BB.
Spine stabilization, thalidomide, celecoxib, interferon-alpha2b, pamidronate, zoledronate, thoracotomy, pleurectomy, talc pleurodesis, and imatinib mesylate.
Lymphatic metastasis contributes to mortality from solid tumors. Whether metastasizing cancer cells reach lymph nodes via intratumor lymphatic vessels is unknown. Padera et al examine functional ...lymphatics associated with mouse tumors expressing normal or elevated levels of vascular endothelial growth factor-C.
We report on the first measurements of definitive depolarization to access gold nanorod (GNR) perturbation and visualize GNR diffusion, distribution and concentration ex vivo, in vitro and in vivo in ...biologically and medically relevant scenarios.
Two-photon microscopy was used to obtain three-dimensional images of the microvasculature of tumors in dorsal chamber preparations. This approach provided the key to fully exploit the potential of in ...vivo models used to study pathophysiology in solid tumors.
The past few decades have produced a wealth of information about the molecular underpinnings ofcancer. Various genes associated with oncogenesis and tumor angiogenesis have been identified, and this ...has led to the development of a wide variety of therapeutic agents. As we enter the post-genomic era, the grand challenges remaining in tumor biology are (i) to discover the relationships between the expression of novel genes and their function in an intact organism and (ii) to deliver newly discovered therapeutics to their targets in vivo in optimal quantities (Jain et al., 2002).
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