Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment

The focus of this review is to provide an overview of the current state of knowledge of molecular mechanisms/processes that control differentiation of vascular smooth muscle cells (SMC) during normal development and maturation of the vasculature, as well as how these mechanisms/processes are altered in vascular injury or disease. A major challenge in understanding differentiation of the vascular SMC is that this cell can exhibit a wide range of different phenotypes at different stages of development, and even in adult organisms the cell is not terminally differentiated. Indeed, the SMC is capable of major changes in its phenotype in response to changes in local environmental cues including growth factors/inhibitors, mechanical influences, cell-cell and cell-matrix interactions, and various inflammatory mediators. There has been much progress in recent years to identify mechanisms that control expression of the repertoire of genes that are specific or selective for the vascular SMC and required for its differentiated function. One of the most exciting recent discoveries was the identification of the serum response factor (SRF) coactivator gene myocardin that appears to be required for expression of many SMC differentiation marker genes, and for initial differentiation of SMC during development. However, it is critical to recognize that overall control of SMC differentiation/maturation, and regulation of its responses to changing environmental cues, is extremely complex and involves the cooperative interaction of many factors and signaling pathways that are just beginning to be understood. There is also relatively recent evidence that circulating stem cell populations can give rise to smooth muscle-like cells in association with vascular injury and atherosclerotic lesion development, although the exact role and properties of these cells remain to be clearly elucidated. The goal of this review is to summarize the current state of our knowledge in this area and to attempt to identify some of the key unresolved challenges and questions that require further study.

Molecular Regulation of Vascular Smooth Muscle Cell Differentiation in Development and Disease

It has become evident that we cannot understand tumour growth without considering components of the stromal microenvironment, such as the vasculature. At the same time, the tumour phenotype determines the nature of the tumour vasculature. Much research is now devoted to determining the impact of angiogenesis on tumour development and progression, and the reciprocal influences of tumour products on the microvasculature. A more detailed understanding of the complex parameters that govern the interactions between the tumour and vascular compartments will help to improve anti-angiogenic strategies-- not only for cancer treatment, but also for preventing recurrence.

Tumorigenesis and the angiogenic switch

The maturation of nascent vasculature, formed by vasculogenesis or angiogenesis, requires recruitment of mural cells, generation of an extracellular matrix and specialization of the vessel wall for structural support and regulation of vessel function. In addition, the vascular network must be organized so that all the parenchymal cells receive adequate nutrients. All of these processes are orchestrated by physical forces as well as by a constellation of ligands and receptors whose spatio-temporal patterns of expression and concentration are tightly regulated. Inappropriate levels of these physical forces or molecules produce an abnormal vasculature--a hallmark of various pathologies. Normalization of the abnormal vasculature can facilitate drug delivery to tumors and formation of a mature vasculature can help realize the promise of therapeutic angiogenesis and tissue engineering.

Molecular regulation of vessel maturation.

Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.

Endothelial cells of tumor vessels have well-documented alterations, but it is less clear whether pericytes on these vessels are abnormal or even absent. Here we report that α-smooth muscle actin (α-SMA) and desmin-immunoreactive pericytes were present on >97% of blood vessels viewed by confocal microscopy in 100-μm-thick sections of three different spontaneous or implanted tumors in mice. However, the cells had multiple abnormalities. Unlike pericytes on capillaries in normal pancreatic islets, which had desmin but not α-SMA immunoreactivity, pericytes on capillary-size vessels in insulinomas in RIP-Tag2 transgenic mice expressed both desmin and α-SMA. Furthermore, pericytes in RIP-Tag2 tumors, as well as those in MCa-IV breast carcinomas and Lewis lung carcinomas, had an abnormally loose association with endothelial cells and extended cytoplasmic processes deep into the tumor tissue. α-SMA-positive pericytes also covered 73% of endothelial sprouts in RIP-Tag2 tumors and 92% of sprouts in the other tumors. Indeed, pericyte sleeves were significantly longer than the CD31-immunoreactive endothelial cell sprouts themselves in all three types of tumors. All three tumors also contained α-SMA-positive myofibroblasts that resembled pericytes but were not associated with blood vessels. We conclude that pericytes are present on most tumor vessels but have multiple abnormalities, including altered expression of marker proteins. In contrast to some previous studies, the almost ubiquitous presence of pericytes on tumor vessels found in the present study may be attributed to our use of both desmin and α-SMA as markers and 100-μm-thick tissue sections. The association of pericytes with endothelial sprouts raises the possibility of an involvement in sprout growth or retraction in tumors.

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Abnormalities in Pericytes on Blood Vessels and Endothelial Sprouts in Tumors

Laparoscopic pelvic lymph node dissection in cadaver surgical training from the combined perspectives of urologists, gastroenterologists and gynecologists improves overall knowledge and technique: initial experience of multidisciplinary cadaver surgical training at a single institution in Japan

As cadaver donor nephrectomy in kidney transplantation is performed in only a limited number of cases, few physicians are skilled in the surgical technique. We performed two cadaver donor nephrectomy sessions during cadaver surgical training. The first session was performed by a lecturer who was skilled in the technique, with physicians and nurses participating in order to learn the methodology. The second session was conducted only for physicians. The procedures undertaken were as follows: cannulation of the femoral artery and vein, skin incision and bowel ligation, cross-clamping of the aorta, diaphragmatic incision and inferior vena cava incision, dissection of the aorta and inferior vena cava, and nephrectomy. Although there were some differences from that normally observed in actual patient surgery, such as no bleeding and formalin fixation, some of the procedures were very useful in helping to better understand cadaver donor nephrectomy.

Toshiyuki Kaidoh

Papers

Abnormalities in Pericytes on Blood Vessels and Endothelial Sprouts in Tumors

Laparoscopic pelvic lymph node dissection in cadaver surgical training from the combined perspectives of urologists, gastroenterologists and gynecologists improves overall knowledge and technique: initial experience of multidisciplinary cadaver surgical training at a single institution in Japan

Experience of Cadaver Donor Nephrectomy with Cadaver Surgical Training.