The present guideline for cell therapy is safe and shows efficacy in patients with SCI, mainly in recovery of sphincter dysfunction, neuropathic pain and sensitivity.
Medullary thyroid carcinoma (MTC) is a malignancy derived from the calcitonin-producing C-cells of the thyroid gland. Oncogenic mutations of the Ret proto-oncogene are found in all heritable forms of MTC and roughly one half of the sporadic cases. However, several lines of evidence argue for the existence of additional genetic lesions necessary for the development of medullary thyroid carcinoma. Sprouty (Spry) family of genes is composed of four members in mammals (Spry1-4). Some Spry family members have been proposed as candidate tumor suppressor genes in a variety of cancerous pathologies. In this work, we show that targeted deletion of Spry1 causes C-cell hyperplasia, a precancerous lesion preceding MTC, in young adult mice. Expression of Spry1 restrains proliferation of the MTC-derived cell line, TT. Finally, we found that the Spry1 promoter is frequently methylated in MTC and that Spry1 expression is consequently decreased. These findings identify Spry1 as a candidate tumor suppressor gene in medullary thyroid carcinoma.
Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinase (RTK) signaling. As such, they restrain proliferation of many cell types and have been proposed as tumor-suppressor genes. Although their most widely accepted target is the Extracellular-regulated kinases (ERK) pathway, the mechanisms by which Spry proteins inhibit RTK signaling are poorly understood. In the present work, we describe a novel mechanism by which Spry1 restricts proliferation, independently of the ERK pathway. In vivo analysis of thyroid glands from Spry1 knockout mice reveals that Spry1 induces a senescence-associated secretory phenotype via activation of the NFjB pathway. Consistently, thyroids from Spry1 knockout mice are bigger and exhibit decreased markers of senescence including Ki67 labeling and senescence-associated b-galactosidase. Although such 'escape' from senescence is not sufficient to promote thyroid tumorigenesis in adult mice up to 5 months, the onset of Phosphatase and tensin homolog (Pten)-induced tumor formation is accelerated when Spry1 is concomitantly eliminated. Accordingly, we observe a reduction of SPRY1 levels in human thyroid malignancies when compared with non-tumoral tissue. We propose that Spry1 acts as a sensor of mitogenic activity that not only attenuates RTK signaling but also induces a cellular senescence response to avoid uncontrolled proliferation. The Sprouty family of genes is composed of four members in mammals (Spry1-4), orthologous to a single Drosophila melanogaster gene (dSpry). With some well-documented exceptions, Sprouty proteins function as feedback inhibitors of receptor tyrosine kinase (RTK) signaling. In Drosophila, dSpry inhibits signaling by FGF and EGF in the airways and the eye, respectively. Genetic experiments in mice establish that Spry1 and Spry2 are negative regulators of signaling by FGFR and Ret RTKs. Thus, the deletion of Spry2 and/or Spry4 causes different craniofacial abnormalities because of hypersensitivity to FGF. On the other hand, excessive Ret signaling underlies kidney and enteric nervous system defects found in Spry1 and Spry2 knockout mice, respectively (reviewed in Guy et al. 1 ). Although the most widely accepted targets of Spry are the ERK MAPK, the mechanisms by which Sprouty proteins restrain signaling by these RTKs remain poorly understood. 1,2 Spry family members have been proposed to function as tumor-suppressor genes in a growing list of cancerous malignancies. Thus, Spry1 and Spry2 levels are decreased in prostate and breast cancer, 3,4 whereas the downregulation of Spry2 has been described in hepatocellular carcinoma, B-cell lymphoma or endometrial carcinoma, among others. [5][6][7] Epigenetic silencing 3,5 or loss of heterozygosity 3 are the most widely observed molecular alterations of the Spry genes in tumoral tissue.In this work, we show that Spry1 null mice exhibit overgrowth of the thyroid gland owing to increased proliferation of thyrocytes. Surprisingly, such increase in cell proliferation does not correlate with eith...
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