RESUMEN
PURPOSE: The development of an altered stromal microenvironment in response to carcinoma is a common feature of many tumors. We reviewed the literature describing characteristics of reactive stroma, how reactive stroma affects cancer progression and how carcinoma regulates reactive stroma. Moreover, we present a hypothesis of reactive stroma in prostate cancer and discuss how the biology of reactive stroma may be used in novel diagnostic and therapeutic approaches. MATERIALS AND METHODS: An extensive literature search was performed to review reports of the general features of wound repair stroma, general stromal responses to carcinoma, and stromal biology of normal and prostate cancer tissues. These studies were analyzed and a reactive stroma hypothesis in prostate cancer was developed. RESULTS: Modifications to the stroma of breast, colon and prostate tumors parallel the generation of granulation tissue in wound repair. These changes include stromal cell phenotypic switching, extracellular matrix remodeling and angiogenesis induction. Therefore, it is predicted that a modified wound healing response induces the formation of reactive stroma in cancer to create a tumor promoting environment. Based on its role in wound repair and its over expression in prostate cancer, transforming growth factor-beta stands out as a potential regulator of reactive stroma. CONCLUSIONS: Reactive stroma in prostate cancer and granulation tissue in wound repair show similar biological responses and processes that are predicted to promote cancer progression. Further identification of specific functional and regulatory mechanisms in prostate cancer reactive stroma may aid in the use of reactive stroma for novel diagnostic and therapeutic approaches.
Asunto(s)
Neoplasias de la Próstata/patología , Progresión de la Enfermedad , Fibroblastos/patología , Sustancias de Crecimiento/fisiología , Humanos , Masculino , Músculo Liso/patologíaRESUMEN
The echinoderm microtubule-associated protein (EMAP) is the most abundant microtubule-binding protein in the first cleavage mitotic apparatus in sea urchin embryos. The first goal of this study was to determine whether there is sufficient EMAP in the egg and embryo to modify microtubule dynamics during the early cleavages divisions and whether EMAP functions at a specific time or place in the embryo. To accomplish this goal, we examined the relative abundance, tissue distribution, and temporal pattern of EMAP expression during embryonic development. The second goal of this study was to identify important functional domains within the EMAP coding sequence. A conserved sequence might reveal a potential microtubule-binding domain. We cloned, sequenced and compared overlapping EMAP cDNAs from two different sea urchin species that diverged approximately 80 million years ago, and compared these with cDNA sequences from a vertebrate and nematode species. From quantitative immunoblots, we determined the EMAP concentration in eggs to be 4 microM. The steady-state levels of EMAP mRNA and protein accumulated during development, and all three germ layers expressed EMAP. During the early stages of development, EMAP and tubulin were both abundant in the ectoderm, mesoderm and endoderm. However, during late gastrulation and the formation of the early pluteus larvae, EMAP was enriched in the mesoderm, while tubulin staining was most abundant in the archenteron. These results indicate that EMAP may have tissue-specific functions in the late stage embryo. To identify conserved functional domains, we compared the predicted amino acid sequence encoded by Strongylocentrotus purpuratus and Lytechinus variegatus EMAP cDNAs, and determined that these two sea urchin EMAPs were 95% conserved and shared an identical domain organization. A parsimonious analysis of these sea urchin protein sequences, as well as human and C. elegans EMAP sequences was used to construct a gene tree. Together these results suggest that EMAP is an important microtubule protein required at all developmental stages of sea urchins, and whose cellular function may be conserved amongst metazoans.
Asunto(s)
Secuencia Conservada , Evolución Molecular , Proteínas Asociadas a Microtúbulos/genética , Secuencia de Aminoácidos , Animales , Caenorhabditis elegans , Humanos , Datos de Secuencia Molecular , Secuencias Repetitivas de Aminoácido , Erizos de Mar , Alineación de SecuenciaRESUMEN
The length of eukaryotic cilia and flagella depends on the cell cycle-regulated assembly and disassembly of at least 9 doublet and 2 central microtubules, their associated proteins, and the surrounding membrane. In light-synchronized Chlamydomonas cells, flagella assembled to 10-14 microm in length near the beginning of the light period and they disassembled prior to cell division, during the dark period. Flagella on light-synchronized pf18 Chlamydomonas mutants grew to 10-12 microm near the beginning of the light period but shortened by 50% or more by the end of the light period. Flagellar length was cell-cycle regulated: when flagella were amputated at various times during the light period, new flagella regenerated to the lengths of control cells at that time of the light cycle. The later in the cycle pf18 cells were deflagellated, the shorter were the regenerated flagella. Flagellar shortening was not affected, in either pf18 or wild-type (wt) cells, by inhibitors of protein synthesis or of microtubule assembly, so flagellar length cannot depend on protein turnover. Shortening in pf18 was attenuated by Li+, which stimulated flagellar growth in wt cells, by red light, by protein kinase inhibitors, and by the Ca2+ channel blockers La3+ and Cd2+. Shortening was increased by cAMP, Na+, K+, and EGTA. Ca2+-CAM blockers did not affect pf18 shortening but they increased shortening in wt and fa1 cells. We propose that flagellar length is regulated by a signal transduction pathway that is sensitive to Ca2+ levels and red light.