Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review focuses on the promising roles of prostate secretory protein of 94 amino acids (PSP-94) and one of its derived peptides (PCK3145) as potential therapeutic modalities for prostate cancer and its associated complications. Evaluation of these compounds was carried out in vitro and in vivo using syngeneic models of rat prostate cancer. Overproduction of parathyroid hormone-related protein (PTHrP) results in the development of hypercalcemia of malignancy in several malignancies including prostate cancer. In order to evaluate the effect of PSP-94 and PCK3145 on prostate cancer progression, the rat Dunning R3227 MatLyLu cell line transfected with full-length cDNA encoding PTHrP (MatLyLu-PTHrP) was used. As the main pathogenetic factor of hypercalcemia of malignancy, overexpression of PTHrP was aimed at mimicking the hypercalcemic nature seen in patients suffering from late-stage cancer. In vitro studies showed that PSP-94 and PCK3145 can cause a dose-dependent inhibition in the growth of MatLyLu-PTHrP cells. For in vivo studies, male Copenhagen rats were inoculated either s.c. into the right flank or directly into the left ventricle via intracardiac (i.c.) inoculation with MatLyLu-PTHrP cells. In these models, s.c. injection of MatLyLu cells results in the development of primary tumor growth, whereas i.c. inoculation routinely results in the development of experimental skeletal metastases in the lumbar vertebrae causing hind-limb paralysis. Administration of PSP-94 and PCK3145 into tumor-bearing animals resulted in a dose-dependent inhibition of primary tumor growth, and tumoral and plasma PTHrP levels, and in the reduction of plasma calcium levels. Additionally, treatment with PSP-94 or PCK3145 caused an inhibition of skeletal metastases resulting in a significant delay in the development of hind-limb paralysis. Interestingly, equimolar concentrations of PCK3145 were shown to be more effective in delaying the development of experimental skeletal metastases as compared to PSP-94. One of the possible mechanisms of action of these modalities is through the induction of apoptosis which was observed by both in-vitro and in-vivo analyses of MatLyLu-PTHrP cells and tumors. Several intracellular mechanisms can also be involved in inhibiting PTHrP production and anti-tumor effects of PSP-94 and PCK3145. Collectively, these studies warrant the continued clinical development of these agents as therapeutic agents for patients with hormone-refractory prostate cancer.
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PMID:Prostate secretory protein of 94 amino acids (PSP-94) and its peptide (PCK3145) as potential therapeutic modalities for prostate cancer. 1622 45

Cadherin-mediated adhesion plays an important role in maintaining cell-cell contacts and reducing tumor metastasis. However, neo-expression of E-cadherin in ovarian carcinoma does not prevent the release and spread of cells from the primary tumor. Because caveolin-1 is down-regulated concomitantly with E-cad expression, we investigated whether the stability of adherens junctions in ovarian carcinoma was affected by caveolin-1 expression. We used IGROV1 cells transfected with caveolin-1 (IGtC3), mock-transfected control cells (IGtM87), and SKOV3 cells that endogenously express caveolin-1. Simultaneous expression of caveolin-1 and E-cadherin favored membrane distribution of E-cadherin and its associated catenin (p120ctn), even when caveolin-1 was only focally associated with adherens junctions. Silencing of caveolin-1 induced intracellular E-cadherin redistribution in IGtC3 and SKOV3 cells. Treatment with the specific src kinase inhibitor PP1 increased E-cadherin expression in IGtM87 and SKOV3 cells and enhanced membrane localization of both E-cadherin and p120ctn. However, PP1 could not completely reverse the detrimental effects on cell-cell adhesion induced by Ca2+ depletion in IGtM87 cells. Together, our data suggest that caveolin-1 expression indirectly promotes cell-cell adhesion in ovarian carcinoma cells by a mechanism involving inhibition of src-related kinases. Thus, down-regulation or loss of caveolin-1 might contribute significantly to the spread of tumor cells from the primary tumor.
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PMID:Simultaneous expression of caveolin-1 and E-cadherin in ovarian carcinoma cells stabilizes adherens junctions through inhibition of src-related kinases. 1625 25

EpCAM is a 40-kDa epithelial transmembrane glycoprotein that has a well-known role in Ca2+ -independent homophilic cell-cell adhesion. Recently, correlations between EpCAM expression and clinicopathological features have been investigated in various cancers. We examined EpCAM expression in surgical specimens from esophageal cancer patients (n = 138), using real-time RT-PCR, immunohistochemistry and ELISA. The mean expression level of EpCAM mRNA in tumor tissues was significantly higher than that in corresponding normal tissues (P < 0.0001). Immunohistochemically, positive staining for EpCAM was found in 135 (97.8%) of the 138 primary tumor specimens. EpCAM expression was correlated with tumor depth (P = 0.0005), stage (P = 0.0037), blood-vessel invasion (P = 0.0397) and infiltrative growth pattern (P = 0.0015). The survival rates of patients with tumors with high EpCAM expression was significantly higher than those for patients with tumors with low EpCAM expression (P = 0.0213). Furthermore, the serum EpCAM levels of patients with esophageal cancer were significantly higher than those of normal volunteers (P = 0.0221). The survival rates of patients with a high EpCAM level in the peripheral vein were also significantly higher than those for patients with a low serum EpCAM level (P = 0.0291). The serum EpCAM level in the peripheral vein was independently associated with prognosis (P = 0.0074; hazard ratio 7.40). Tumor-specific EpCAM expression and release into the circulation may serve as effective immunotherapy in esophageal cancer patients.
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PMID:Prognostic significance of EpCAM expression in human esophageal cancer. 1714 26

The objective of this study was to determine our institutional experience with cytoreductive nephrectomy alone or in conjunction with nephrectomy complete metastasectomy. Between July 1989 and September 2003, we queried our department's renal tumor database for patients undergoing cytoreductive nephrectomy alone or in conjunction with complete metastasectomy. Clinical and pathological factors analyzed included primary tumor size, stage and histological subtype, age, gender, Karnofsky Performance Status (KPS) prior to nephrectomy, number and location of metastatic sites, and the presence or absence of any systemic therapy. Preoperative laboratory values analyzed included hemoglobin (HGB), calcium (CA), albumin (ALB), lactose dehydrogenase (LDH), alkaline phosphatase (ALP), and corrected calcium. Corrected calcium was defined as follows: corrected calcium = total calcium-0.707*(albumin-3.4). During this time frame,1628 patients underwent nephrectomy (partial or radical) for renal masses, 91 (5.6%) of whom had metastatic disease. In this group, 71% of patients were male, 88% of patients had a KPS of 80% or greater, and 92% had conventional clear cell histology. Sixty-four percent of patients had a single site of metastatic disease, with lung the most common, followed by bone, adrenal, brain, and liver. Sixty-one patients (67%) had nephrectomy with removal of all metastatic sites (nephrectomy/complete metastasectomy) and 30 (33%) had cytoreductive nephrectomy alone. Median survival for patients undergoing nephrectomy/complete metastasectomy was 30 months. Median survival for patients undergoing cytoreductive nephrectomy alone was 12 months. Perioperative complications occurred in 13% of patients and four patients died within 30 days of their operation. For patients with metastatic renal cell carcinoma, surgical resection of the primary tumor alone (cytoreductive nephrectomy) or in conjunction with metastasectomy can be accomplished with acceptable perioperative morbidity and mortality. This surgical experience provides a contemporary foundation as new targeted therapeutic agents are integrated into the neoadjuvant or adjuvant treatment of locally advanced and metastatic renal cancer.
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PMID:Cytoreductive nephrectomy and nephrectomy/complete metastasectomy for metastatic renal cancer. 1761 59

Expression of the chemokine receptor CXCR4 has been linked with increased metastasis and decreased clinical prognosis in breast cancer. The current paradigm dictates that CXCR4 fosters carcinoma cell metastasis along a chemotactic gradient to organs expressing the ligand CXCL12. The present study asked if alterations in autocrine CXCR4 signaling via dysregulation of CXCL12 in mammary carcinoma cells modulated their metastatic potential. While CXCR4 was consistently detected, expression of CXCL12 characteristic of human mammary epithelium was silenced by promoter hypermethylation in breast cancer cell lines and primary mammary tumors. Stable re-expression of functional CXCL12 in ligand null cells increased orthotopic primary tumor growth in the mammary fat-pad model of tumorigenesis. Those data parallel increased carcinoma cell proliferation measured in vitro with little-to-no-impact on apoptosis. Moreover, re-expression of autocrine CXCL12 markedly reduced metastatic lung invasion assessed using in vivo bioluminescence imaging following tail vein injection. Consistent with those data, decreased metastasis reflected diminished intracellular calcium signaling and chemotactic migration in response to exogenous CXCL12 independent of changes in CXCR4 expression. Together these data suggest that an elevated migratory signaling response to ectopic CXCL12 contributes to the metastatic potential of CXCR4-expressing mammary carcinoma cells, subsequent to epigenetic silencing of autocrine CXCL12.
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PMID:Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells. 1772 66

Bone marrow-derived cells, which are recruited to peripheral tissues, have been shown to play a major role as angiogenic factor supplier. Moreover, bone marrow-derived "hemangiocytes" through graded chemokines production, can function as the molecular hub for hematopoietic cytokine-induced neovascularization. Current focus on cancer metastasis has centered on the intrinsic factors regulating the cell autonomous homing of the tumor cells to the metastatic site : Bone marrow-derived cells expressing vascular endothelial growth factor receptor 1 can be mobilized into the circulation due to growth factors released by the primary tumor. These cells cluster at distant sites, "the premetastatic niche" , where they set up a microenvironment ideal for tumor cells to seed, thereby completing the metastatic spread. Focus on the early cellular and molecular events in cancer infiltration, metastasis and proliferation will likely lead to new approaches to detect and prevent metastasis at its earliest inception.
Clin Calcium 2008 Apr
PMID:[Bone marrow-derived cells contribute to niche formation in cancer progression]. 1837 30

Gastrinoma tissue has been found frequently in lymph nodes located near the duodenum without a known primary tumor. Therefore, it has been suggested that a primary lymph node gastrinoma exists. We report on a 38-year-old woman suffering from multiple endocrine neoplasia type 1 (MEN1) confirmed by menin gene mutation analysis. MEN1 disease started with primary hyperparathyroidism followed by Cushing disease, the detection of tumors of the pituitary, adrenal cortex, and the pancreas and also an elevated serum gastrin level. An octreotide scan revealed 4 tumors in the upper abdomen. A selective arterial calcium stimulation test located the source of the hypergastrinemia to the area of the gastroduodenal and the superior mesenteric arteries. Total pancreatoduodenectomy was performed and conventional histopathologic examination revealed a well-differentiated cystic neuroendocrine tumor of the pancreas expressing glucagon and accompanied by several microadenomas. In addition, 3 suprapancreatic lymph nodes with gastrin-positive endocrine tissue were found. None of the pancreatic microadenomas expressed gastrin and no duodenal endocrine tumor was found despite careful macroscopic examination. Only after complete embedding of the duodenal and pancreatic tissue in 65 paraffin blocks, 2 microgastrinomas (0.45 and 0.8 mm in diameter) were identified in the duodenum. It is concluded that duodenal gastrinomas that give rise to lymph node metastases may be so tiny that they are easily overlooked in a routine examination and that systematic tissue monitoring is required to identify them.
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PMID:Primary lymph node gastrinoma or occult duodenal microgastrinoma with lymph node metastases in a MEN1 patient: the need for a systematic search for the primary tumor. 1852 Apr 36

Hypercalcemia of malignancy carries an extremely grim prognosis. The most common mechanism underlying hypercalcemia of malignancy is production by the tumor cells of cytokines responsible for osteoclastic differentiation and, therefore, lysis of the bone adjacent to the tumor. A minority of cases are attributable to increased renal reabsorption of calcium caused by a humoral factor, termed parathyroid hormone-related peptide, which is produced by some primary tumors. These two mechanisms can be involved in conjunction, particularly in patients with breast cancer. The development of osteolytic metastases initiates a vicious cycle in which bone degradation products, especially growth factors, stimulate the growth of the tumor cells located at the bone-tumor interface. Parathyroid hormone-related peptide is produced by many malignant tumors, most notably those of the breast. In addition to its endocrine effect on the kidney, it may have a paracrine effect consisting of enhancement of osteoclastic differentiation with osteolysis of the bone adjacent to the tumor. Other factors produced by primary tumor cells, such as proteases, intercellular adhesion molecules, or bone matrix proteins, may influence the propensity for the tumor to produce bone metastases. Bisphosphonates are usually effective in inducing a remission of hypercalcemia of malignancy and in improving the clinical manifestations of osteolytic metastases. Elucidation of the factors that influence the propensity for malignancies to metastasize to bone would improve our ability to use bisphosphonates optimally as adjuncts to tumor therapy.
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PMID:Role of Parathyroid Hormone Related Peptide (PTHrP) in Hypercalcemia of Malignancy and the Development of Osteolytic Metastases. 1907 66

We report a 47-year-old women who presented to her general practitioner and our hospital with weight loss of unknown etiology. Eight years previously she had undergone a hemithyroidectomy for nodular goiter with one cold nodule. Laboratory results revealed hypercalcemia, evidence of primary hyperparathyroidism and computer tomography of the thorax showed bilateral pulmonary metastasis. After undergoing CT-guided biopsy of a metastasis, histology revealed an endocrine primary tumor with low parathyroid hormone expression. In view of the history, clinical and biochemical findings we diagnosed a recently metastasized functioning parathyroid carcinoma, which eight years previously has been labeled as a benign atypical thyroid adenoma. The patient underwent surgical resection of all detected metastases. Afterwards the serum calcium and parathyroid hormone levels normalized. Parathyroid carcinoma is an uncommon tumor. In the absence of pathognomonic diagnostic criteria a definitive pathological diagnosis of parathyroid carcinoma often is not possible. The treatment of parathyroid carcinoma is essentially surgical. Patients with parathyroid carcinoma mostly die from uncontrollable hypercalcemia rather than from other tumor-related complications.
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PMID:[Rare cause of hypercalcemia]. 1921 66

Sarcoidosis is a granulomatous disease of unknown origin, with pulmonary findings in more than 90% of patients. Extrapulmonary involvement is common and all organs can be involved (especially lymph nodes, eyes, joints, central nervous system) but it is rare to find an isolated extrapulmonary disease (less than 10% of patients). Granulomatous inflammation of the spleen and the liver is common in patients with systemic sarcoidosis, while hepatosplenic enlargement is unusual and splenic involvement rare. We report two cases of systemic sarcoidosis, that onset with splenic and hepatosplenic disease, and one case with splenic sarcoidosis without pulmonary involvement. In the first case a 53-year-old woman with mild abdominal pain underwent sonography and CT, which revealed one hypoechoic/hypodense splenic lesion. Laboratory tests were normal. In order to exclude a lymphoma, splenectomy was performed: histology revealed a sarcoid granuloma. After surgery the patient was asymptomatic and now, after two years, disease is silent. The second case is a 66-year-old woman with a recent weight loss (8 kg in two months) and alterated liver function tests (AST 61 U/l, ALT 72 U/l, Alkaline phosphatase 748 U/l, g-GT 381 U/l). Since she had a familiar history of colon cancer, abdominal US scan, abdominal CT scan and MRI were performed and showed inter-aorto-caval lymphadenopathies and discreet multiple bilobar hepatic and splenic substitutive lesions, with no signs of primary tumor. Upper and lower GI endoscopy, full gynecological workup, complete set of tumor markers, bone marrow biopsy were performed. All resulted negative for neoplasia. Small pulmonary infiltrations were observed on chest-CT scan but cytology on BAL was normal. Infections were also excluded. An exploratory laparotomy showed whitish peritoneal, hepatic and splenic nodules. The histological exam revealed chronic granulomatous lesions typical for sarcoidosis. During a two-year follow-up after the splenectomy the patient feels well without any treatment. The third patient is a 32-year-old woman with mild epigastric pain after meals. Neck-thoracic CT, bone scintigraphy and upper GI endoscopy were negative. Abdominal US and MR showed splenomegaly with multiple splenic lesions. Splenectomy was performed and histological exam showed chronic granulomatous lesions typical for sarcoidosis. Further laboratory tests were normal, except for ACE (66 UI/l). After the surgery ACE became normal and now, three years later, the patient is still asymptomatic. We conclude that hepatosplenic involvement is less rare than it is thought. It is often oligosymptomatic or accompanied with unspecific manifestations and laboratory abnormalities. The diagnosis could be difficult; in fact typical laboratory findings of sarcoidosis such as ACE, lysozyme, calcium, were not diagnostic. Ultrasonography and CT were important but the diagnosis was established only with the histological examination of suspected lesions. This latter required to differentiate liver and/or spleen sarcoidosis from tuberculosis and other infections, primary biliary cirrhosis, metastasis or malignant lymphoma.
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PMID:Atypical sarcoidosis: case reports and review of the literature. 2138 7


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