Distant Organ Sites Research Articles

Is Prostate Cancer Screening Analogous to Lung Cancer Screening?

To the Editor. —Is prostate cancer more like breast cancer or lung cancer? For reasons that are hard to fathom, Drs Collins and Barry 1 feel that it is more like lung cancer. They dismiss the parallels between prostate cancer screening and breast cancer screening without comment and then focus on the flawed studies in lung cancer that failed to demonstrate a survival benefit. 2 In doing so, they conveniently ignore 2 major flaws in their own logic. First is tumor biology. Prostate cancer is characterized by a slow, natural progression of the disease, 3 whereas the clinical course of lung cancer is frequently established before it can be seen on x-ray examination. For example, by the time the diagnosis of small cell carcinoma of the lung is established, dissemination to distant organ sites has almost always occurred. 4 In lung cancer studies, small cell cancer has comprised 25% of cases. 2 This

Borrelia burgdorferi induces secretion of pro-urokinase-type plasminogen activator by human monocytes

Borrelia burgdorferi is transmitted by infected ticks and causes Lyme disease. To infect distant organ sites, B. burgdorferi spirochetes must disseminate from the site of the tick bite. During dissemination from the dermal tissue, they breach tissue barriers, probably by proteolysis. The previous findings that spirochetes bind serum-derived plasminogen and that plasmin favors spirochetal invasiveness and infectivity suggested a role for plasmin in the pathogenicity of B. burgdorferi. Binding of plasminogen to spirochetes and activation into plasmin is favored in a microenvironment that is rich in plasminogen and plasminogen activators. Plasminogen is abundant in plasma and interstitial fluids, and it is increased in inflammatory exudates. Since B. burgdorferi does not express endogenous plasminogen activators, the conversion of spirochete-bound plasminogen depends on host-derived plasminogen activators. In this report, we show that both intact B. burgdorferi organisms and its recombinant outer surface lipoprotein A induce human monocytes to express and secrete urokinase-type plasminogen activator in its zymogen form (pro-uPA). Moreover, we demonstrate that the presence of B. burgdorferi accelerates the interaction between (pro-)uPA and plasmin(ogen), leading to spirochete-bound plasmin. In a pro-uPA-serum mixture, spirochete-bound plasmin activity is generated. Taken together, the data suggest that B. burgdorferi may induce pro-uPA in a monocyte-containing inflammatory site and that the spirochetal surface provides an appropriate milieu for subsequent interactions between (pro-)uPA and plasmin(ogen), which result in spirochete-bound plasmin even in the presence of inhibitors for plasminogen activators and plasmin.

Identification of genetic alterations associated with the process of human experimental colon cancer liver metastasis in the nude mouse

Understanding the genetic elements controlling the process of tumor metastasis to distant organ sites such as the liver may be the key to improving survivorship from colon cancer. By using standard cytogenetic techniques in combination with comparative genomic hybridization, multiple genetic imbalances within three human colon cancer cell lines previously selected for differences in liver-metastatic behavior were identified. The entire genome of one poorly metastatic cell line (KM12C) was compared directly with that of two highly metastatic cell lines (KM12SM, KM12L4A) derived from it. A number of chromosomal gains (8q, 12q15, 20q11.2) and losses (5p13, 6p21.3, 18) were common to all three cell lines and are likely related to early tumor development rather than to the selection process used to generate cell lines of increased metastatic potential. Chromosomal imbalances detected only in the highly metastatic cell lines were also observed. KM12SM showed losses of portions of 2p22, 2q24.3--> 2q32.2, 4p15.3--> cen, 4q24 without the 13q and 15q22.3 gains noted for KM12C. Both gains (1p31.3--> 1p21, 2q22--> 2q33, 3cen--> 3q26.2, 5q14--> 5q23, 6cen--> 6q23) and losses (16p, 17p, 17q 19p, 19q 22q) were observed for KM12L4A but not for the other two cell lines. Identification of these alterations provides valuable insight into the process of experimental liver metastasis and is a first step towards mapping genes linked to the terminal phases of human colon cancer progression.

Up-Regulation of TNFα mRNA in the Rat Spleen Following Induction of Acute Pancreatitis

Tumor necrosis factor-alpha (TNFα) is postulated to be a mediator of the systemic complications associated with acute pancreatitis. Neutralization of TNFα with monoclonal antibody ameliorates the morbidity and mortality associated with acute pancreatitis in a rat model. Although high levels of TNFα are measurable in peripheral blood in acute pancreatitis, specific sites of TNFα production in this disease have not been described. In this study we show that induction of pancreatitis causes up-regulation of TNFα messenger RNA (mRNA) at a distant organ site, the spleen. Hemisplenectomies were performed in male Sprague-Dawley rats prior to induction of pancreatitis by pancreatic duct infusion of artificial bile. Completion hemisplenectomies were then performed at 30 min, 1 hr, and 2 hr after pancreatitis induction. Quantitation of TNFα mRNA in the hemispleens before and after pancreatitis using a semiquantitative reverse transcriptase-polymerase chain reaction method revealed an 80-fold increase in amount of TNFα mRNA by 2 hr after induction of pancreatitis. By contrast, control rats receiving a sham operation showed no significant increase in TNFα mRNA expression after infusion of the pancreatic duct with saline. The increase in TNFα mRNA production was associated with increased serum TNFα product levels and was independent of endotoxin. We conclude that severe acute pancreatitis in the rat model is associated with significant up-regulation of TNFα mRNA in splenic mononuclear cells. These data provide evidence that the local events of acute pancreatitis can induce up-regulation of TNFα mRNA at a distant site and suggest a possible mechanism of pathogenesis of the systemic manifestations of this disease.

Tumor cell interactions with the vascular endothelium and their role in cancer metastasis.

The prevention of cancer deaths is dependent upon understanding the mechanism of malignant tumor cell spread from primary tumor sites to distant organ sites. Cancer metastases form by way of a complex series of sequential steps involving a variety of tumor cell and host properties. These steps typically involve growth and invasion of malignant cells at primary sites, followed by their penetration into lymphatics and blood circulation and body cavities. Once in these compartments, the malignant cells can detach and be transported to distant sites. There they can implant and invade surrounding tissues, and establish suitable microenvironments for survival and growth. This chapter will deal with the importance of tumor cell-endothelial interactions in the metastatic process.KeywordsEndothelial CellMicrovascular Endothelial CellMetastatic CellMetastatic Tumor CellEndothelial Cell SurfaceThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Interleukin-6 undergoes transition from paracrine growth inhibitor to autocrine stimulator during human melanoma progression.

The ability to penetrate the dermal basement membrane and subsequently proliferate in the underlying mesenchyme is one of the key steps in malignant progression of human melanomas. We previously undertook studies aimed at assessing how normal dermal fibroblasts (one of the main cellular components of mesenchyme) may affect the growth of human melanoma cells and facilitate the overgrowth of malignant subpopulations (Cornil, I., D. Theodorescu, S. Man, M. Herlyn, J. Jambrosic, and R. S. Kerbel. 1991. Proc. Natl. Acad. Sci. USA. 88:6028-6032). We found that melanoma cell lines from early-stage (metastatically incompetent) lesions were growth inhibited whereas those from advanced-stage (metastatically competent) lesions were stimulated under the same conditions by co-culture with fibroblasts; conditioned medium from such cells gave the same result. Subsequent studies using biochemical purification and neutralizing antibodies revealed the inhibitory activity to be identical to interleukin-6 (IL-6). We now report that addition of purified recombinant human IL-6 resulted in a growth inhibition in vitro by G1/G0 arrest of early, but not advanced stage melanoma cells. Despite this alteration in response there was no significant difference in melanoma cell lines of varying malignancy in respect to their expression of genes encoding the IL-6 receptor, or gp130, the IL-6 signal transducer. Scatchard analysis also revealed similar [125I]IL-6 binding activities in both IL-6 sensitive and resistant groups. However, studies of IL-6 production indicated that five out eight IL-6 melanoma cell lines known to be resistant to exogenous IL-6-mediated growth inhibition constitutively expressed mRNA for IL-6; they also secreted bioactive IL-6 into culture medium. To assess the possible role of this endogenous IL-6 in melanoma cell growth, antisense oligonucleotides to the IL-6 gene were added to cultures of melanoma cells. This resulted in a significant growth inhibition only in cell lines that produced endogenous IL-6. In contrast, neutralizing antibodies to IL-6 were ineffective in causing such growth inhibition. This indicates that endogenous IL-6 may behave as a growth stimulator by an intracellular ("private") autocrine mechanism. Thus, a single cytokine, IL-6, can switch from behaving as a paracrine growth inhibitor to an autocrine growth stimulator within the same cell lineage during malignant tumor progression. Such a switch may contribute to the growth advantage of metastatically competent melanoma cells at the primary or distant organ sites and thereby facilitate progression of disease.

The role of the gut in the development of sepsis in acute pancreatitis

The pathogenesis of sepsis in acute pancreatitis is unknown. Since the intestinal tract has recently been identified as a possible source for sepsis in other conditions, we explored whether the gut may serve as a reservoir for bacteria causing systemic and pancreatic infection in acute pancreatitis. Bacterial translocation, alterations of intestinal microflora, and intestinal motility, as reflected by gut propulsion, were studied in a rat pancreatitis model. Acute pancreatitis was induced by biliopancreatic obstruction (AP); sham manipulated animals served as controls (sham). Bacteriologic cultures were obtained from various segments of the intestinal tract and from blood, liver, spleen, pancreas, and mesenteric lymph nodes 48 and 96 hr after induction of AP or sham. Bacteria were recovered from mesenteric lymph nodes of all 12 animals with AP, but only from 3 14 sham animals ( P < 0.05). Spread to distant organ sites occurred in 4 of 12 animals with AP compared to none of the sham animals ( P < 0.05). A disruption of the intestinal microflora was found in the cecum, where the gram-negative bacterial count (log/g) was significantly higher during AP when compared with sham controls: 10.62 ± 1.04 vs 8.05 ± 1.45 at 48 hr and 7.92 ± 0.62 vs 6.79 ± 0.87 at 96 hr, respectively. In addition, the gram-negative bacterial population was also significantly increased in the duodenum of animals with AP after 96 hr as compared to sham: 5.10 ± 0.97 vs 3.94 ± 0.81. Small bowel propulsion was studied 24 hr after induction of AP or sham by injecting fluorescent-labeled dextrans into the duodenum and measuring the distance that the dextrans migrated distally after various time periods. The mean reduction of gut propulsion was 55% at 25 min, 34% at 60 min, 36% at 120 min, and 27% at 240 min. These data implicate the gut as an important source for infection during acute pancreatitis. A possible mechanism for the development of sepsis appears to be decreased gut motility followed by a disruption of the indigenous microflora with subsequent promotion of bacterial translocation to mesenteric lymph nodes and distant sites.

Influence of Organ Environment on Extracellular Matrix Degradative Activity and Metastasis of Human Colon Carcinoma Cells

Orthotopic implantation of human colon carcinoma cells is useful for studying the behavior of metastatic subpopulations. We observed that the parental line and variants of human colon carcinoma KM12 cells were all tumorigenic following implantation into the subcutis or cecal wall of BALB/c nude mice. Their ability to metastasize to distant organ sites varied, however, with the site of growth. Subcutaneous (SC) tumors did not produce visceral metastases, whereas cecal tumors metastasized to the regional mesenteric lymph nodes and to the liver. To examine the influence of organ environment on the extracellular matrix-degrading activity of the tumors, we inoculated human colon carcinoma cells into the subcutis or cecal wall and after 7 weeks isolated and cultured the tumors in serum-free medium. The conditioned media of SC tumors contained very low levels of type IV collagenase (gelatinase) and heparanase (heparan sulfate-specific endo-beta-D-glucuronidase), whereas the media of the cecal wall tumors contained high levels of both. Zymograms of the media revealed that the intracecal human colon carcinomas secreted more than three times the amount of latent and active forms of 92-kd type IV collagenase than did the SC tumors. Moreover, only the conditioned media of intracecal tumors contained latent and active forms of 64-kd type IV collagenase. Histochemical analysis using rabbit antiserum raised against the synthetic peptides of 72-kd procollagenase type IV showed type IV collagenase in the intracecal tumors; human colon carcinoma growing SC, however, were not stained significantly. These results suggest that factors in the organ environment may affect production and secretion of tumor extracellular matrix-degrading enzymes, and these factors may modify the metastatic behavior of human colon carcinoma cells in nude mice.

The role of histopathology in the diagnosis and management of uveitis

Intraocular inflammation/uveitis is one of the more poorly understood areas in the field of ophthalmology. We hope to improve this understanding by first reviewing the classic histopathologic approach to intraocular inflammation, and then by integrating that with the current role of histopathology in the diagnosis and management of uveitis. Herein, we will present a systematic approach, beginning with the most accessible conjunctival, lacrimal gland and lymph node biopsy sites; extending through anterior chamber tap, iris biopsy, and vitrectomy and ending with retinal or chorioretinal biopsy of distant organ sites. We will show how a combination of these histopathologic elements can aid in the diagnosis, and thereby the management, of intraocular inflammations and uveitis.