Anticancer potential of new 3-nitroaryl-6-(N-methyl)piperazin-1,2,4-triazolo[3,4-a]phthalazines targeting voltage-gated K+ channel: Copper-catalyzed one-pot synthesis from 4-chloro-1-phthalazinyl-arylhydrazones.

A series of six 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines were prepared through a facile and efficient one-pot copper-catalyzed procedure from 4-chloro-1-phthalazinyl-arylhydrazones with relatively good yields (62-83%). The one-pot copper-catalytic procedure consists of two simultaneous reactions: (i) a direct intramolecular dehydrogentaive cyclization between ylidenic carbon and adjacent pyrazine nitrogen to form 1,2,4-triazolo ring and, (ii) a direct N-amination on carbon-chlorine bond. Then, an in vitro anticancer evaluation was performed for the synthesized compounds against five selected human cancer cells (A549, MCF-7, SKBr3, PC-3 and HeLa). The nitro-derivatives were significantly more active against cancer strains than against the rest of tested compounds. Specifically, compound 8d was identified as the most promising anticancer agent with significant biological responses and low relative toxicities on human dermis fibroblast. The cytotoxic effect of compound 8d was more significant on PC3, MCF-7 and SKBr3 cancer cells with low-micromolar IC50 value ranging from 0.11 to 0.59 µM, superior to Adriamycin drug. Mechanistic experimental and theoretical studies demonstrated that compounds 8d act as a K+ channel inhibitor in cancer models. Further molecular docking studies suggest that the EGFR Tyrosine Kinase enzyme may be a potential target for the most active 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines.

Anti-leishmanial effect of spiro dihydroquinoline-oxindoles on volume regulation decrease and sterol biosynthesis of Leishmania braziliensis.

Diverse spiro dihydroquinoline-oxindoles (JS series) were prepared using the BF3•OEt2-catalyzed imino Diels-Alder reaction between ketimine-isatin derivatives and trans-isoeugenol. Ten spiro-oxiindole derivatives were selected and evaluated at different stages of the life cycle of Leishmania braziliensis parasites, responsible for cutaneous leishmaniasis in South America. Among them, the 8'-ethyl-4'-(4-hydroxy-3-methoxyphenyl)-3'-methyl-3',4'-dihydro-1'H-spiro[indoline-3,2'-quinolin]-2-one called JS87 was able to inhibit the growth of promastigotes without affecting the mammalian cells viability, and to decrease the number of intracellular amastigotes of L. braziliensis. This spiro compound was found to act through the alteration of parasite internal regulation by disrupting the regulatory volume decrease (RVD), and to affect the sterol biosynthetic pathway at level of squalene epoxidase (SE) enzyme. These results revealed that the spiro annulation between quinoline and oxindole scaffolds enhances the anti-leishmanial activity, and could assist in the development of potent quinoline-oxindole hybrids against Leishmania braziliensis, the main etiological agent of cutaneous leishmaniasis in South America.

[Contamination, endocrine disruptors and cancer]. / Contaminación, disruptores endocrinos y áfincer.

Since the mid-twentieth century, many species, very different from each other and located in all areas and comers of the planet, began presenting various alterations, many of which suggested to be related to endocrine disorders. Research has shown that such alterations were caused by exposure to various chemical contaminants that could affect the health and cause serious illnesses. Among them stands a diverse and large group of compounds, with very different chemical structures, capable of altering the hormonal balance, act at very low doses and with different mechanisms of action, that are called "endocrine disrupting chemicals". When released into the environment or as part of objects, food or medicines, constitute a major risk to animals and humans, which produces not only endocrine dysfunctions but also different cancers, which include the most common types. Despite the importance and significance of the impact of these compounds, they are not sufficiently known or understood, so the aim of this review is to show their origin and impact in the field of human health, highlighting their role as inducers of cancer, which has led to multiple clinical and biological investigations.

[Stem cells and cancer]. / Células madre y cáncer.

Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Cancer stem cells are a subpopulation of the cells that form the tumor. The discovery of these human cancer cells opens a perspective for understanding tumor recurrence, drug resistance and metastasis; and opens up new research directions on how cancer cells are capable of switching from dormancy to malignancy. Therapeutic alternatives emerge from a better understanding of the biology and the environment of tumor stem cells. The present paper aims to summarize the characteristics and properties of cancer stem cells, the ongoing research, as well as the best strategies for prevention and control of the mechanisms of tumor recurrence.

Anti-leishmanial evaluation of C2-aryl quinolines: mechanistic insight on bioenergetics and sterol biosynthetic pathway of Leishmania braziliensis.

A series of diverse simple C2-aryl quinolines was synthesized de novo via a straightforward synthesis based on the acid-catalyzed multicomponent imino Diels-Alder reactions. Seven selected quinolines were evaluated at different stages of Leishmania braziliensis parasite. Among them, the 6-ethyl-2-phenylquinoline 5f was able to inhibit the growth of promastigotes of this parasite without affecting the mammalian cells viability and decreasing the number of intracellular L. braziliensis amastigotes on BMDM macrophages. The mechanism of action studied for the selected compound consisted in: (1) alteration of parasite bioenergetics, by disrupting mitochondrial electrochemical potential and alkalinization of acidocalcisomes, and (2) inhibition of ergosterol biosynthetic pathway in promastigote forms. These results validate the efficiency of quinoline molecules as leishmanicide compounds.

[Micrometastases: strategies for detection]. / Micrometástasis: estrategias para su detección.

Micrometastasis or minimal residual disease has become critically important in oncology since it represents a true clinical problem that must be solved, as the response of these tumor foci to the different treatments that are used for the control of cancer, is still unknown. Even though this is a fundamental specific problem to be solved, there are already immunohistochemical and molecular biology diagnostic methods that have allowed microfoci location of tumor cells in various organs and tissues, and different techniques are available to determine and quantify these lesions. Within these techniques, flow cytometry and different molecular methods are included, and they range from the traditional to the newest and most sophisticated. The goal of this review was aimed to evaluate new diagnostic methods that permit the identification of this residual disease, which would serve to establish individualized treatments and prevent the recurrence of the disease in cancer patients under treatment.

[Limbal deficiency syndrome]. / Sindrome de Insuficiencia Limbal.

The cornea, the transparent tissue of the eye, is formed by an epithelium of five distinct layers that is in continual renewal through a population of limbocorneal stem cells located in the basal layer. Its normal activity depends on a variety of intrinsic and extrinsic factors, that altered, can lead to partial or total loss of progenitor cells leading to a progressive loss of vision. This article reviews the importance of this crippling disease, constituting a major health problem. Several techniques have been developed, but the transplant of the limbus using autograft or allograft accompanied by a treatment to suppress inflammation and neovascularization is still the most widely used. At present, this procedure is being replaced by the new techniques of tissue engineering, which have multiple benefits, such as more safety, efficiency, elimination of the risks of rejection, decrease of time of treatment and lower costs. The use of limbal cells cultures has made possible to develop a more secure and refined technology. In this review we emphasize one of these techniques, which has proven to be very effective and advantageous to produce the epithelium of the cornea in vitro.

The natural diterpene ent-16ß-17α-dihydroxykaurane down-regulates Bcl-2 by disruption of the Ap-2α/Rb transcription activating complex and induces E2F1 up-regulation in MCF-7 cells.

ent-Kauranes are diterpene-type compounds commonly found in most plant species, especially from the Euphorbiaceae family. These compounds have been studied due to their anti-inflammatory and anti-tumor properties. Regulation of apoptosis, or programmed cell death, is commonly bypassed by tumoral cells, giving rise to uncontrolled proliferating cells, which eventually become carcinogenic. In a previous work, we showed that both mRNA and protein expression levels of the antiapoptotic gene Bcl-2 are reduced in MCF-7 cancer cells by the effect of the natural diterpene ent-16ß-17α-dihydroxykaurane (DHK). This effect was not directly associated with the inactivation of NF-κB, as has been shown with other diterpenes compounds. Herein, we report that DHK is dissociating the Ap2α-Rb activating complex, affecting its binding ability for the Bcl-2 gene promoter. These events down-regulate Bcl-2 and is temporally accompanied by the induction of E2F1 and its target pro-apoptotic gene Puma. Disruption of the Rb-Ap2α activation complex was corroborated by chromatin immunoprecipitation and protein immunolocalization, which also revealed that Ap2α sorts out from the nucleus and relocalizes in the cell periphery. Taken together, our study confirms the regulation of Bcl-2 gene transcription by the Ap2α-Rb complex and describes a singular protein relocalization for Ap2α induced by DHK, implicating a new potential therapeutic target to differentially onset apoptosis in tumor cells.

[Prostate cancer and apoptosis]. / Cáncer de próstata y apoptosis.

Prostate cancer presents an androgen-dependent growth mediated by the androgen receptor (AR). Androgen pathway blockage is the standard therapy for the treatment of prostate cancer at an advanced stage. In spite of an initial sensitivity, prostate cancer usually becomes refractory to hormone treatment. This resistance can be due to the amplification of the AR gene, AR mutations and the increase in co-activator protein expression. Likewise, growth factors and cytokines can induce AR phosphorylation, independently of ligand fixation. Moreover, there are other AR-independent pathways, such as the acquisition of the neuroendocrine phenotype. In this review, we examine the molecular mechanisms that are involved in the progression of prostate cancer, as well as the ways its cells evade apoptosis.

Clinical relevance of human cancer xenografts as a tool for preclinical assessment: example of in-vivo evaluation of topotecan-based chemotherapy in a panel of human small-cell lung cancer xenografts.

Prediction of human tumor response based on preclinical data could reduce the failure rates of subsequent new anticancer drugs clinical development. Human small-cell lung carcinomas (SCLC) are characterized by high initial sensitivity to chemotherapy but a low median survival time because of drug resistance. The aim of this study was to evaluate the therapeutic relevance of a panel of human SCLC xenografts established in our laboratory using one compromising drug in SCLC, topotecan (TPT). Six SCLC xenografts derived from six patients were used: three were sensitive to a combination of etoposide (VP16), cisplatin (CDDP), and ifosfamide (IFO), and three were resistant, as published earlier. Growth inhibition was greater than 84% for five xenografts at doses of 1-2 mg/kg/day. TPT was combined with IFO, etoposide (VP16), and CDDP. IFO improved the efficacy of TPT in three of the five xenografts and complete responses were obtained even with the less TPT-sensitive xenograft. VP16 increased the efficacy of two of four xenografts and complete responses were obtained. The combination of TPT and CDDP did not improve TPT responses for any of the xenografts tested. Semiquantitative reverse transcriptase-PCR of genes involved in drug response, such as topoisomerase I, topoisomerase IIalpha, multidrug resistance 1 (MDR1), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), and glutathione S-transferase pi (GSTpi), did not explain the variability in drug sensitivity between SCLC xenografts. In conclusion, these preclinical data mirror those from published clinical studies suggesting that our panel of SCLC xenografts represents a useful tool for preclinical assessment of new treatments.

Synthesis of dihydroisoindolo[2,1-a]quinolin-11-ones, their in silico ADMET properties and in vitro antitumor activities.

We evaluated the antitumoral activity of diverse series of 5-aryl-dihydroisoindolo[2,1-a]quinolin-11-ones, AIIQ (Aryl IsoIndolo-Quinoline, 4a-m), and 5-vinyl dihydroisoindolo[2,1-a]quinolin-11-ones, VIIQ (Vinyl IsoIndolo-Quinoline, 6a-l), obtained using three component imino Diels-Alder (DA) reaction of anilines, o-phthalaldehyde and dienophiles. The first series was obtained in previous work employing isoeugenol and anethole as dienophiles, whereas the vinyl series was synthesized in high yields (75-90%) using isoprene as a dienophile. The cytotoxic activity of both AIIQ and VIIQ series was evaluated against four cancer lines, identifying a new lead compound 4h from the AIIQ series, active against MCF-7 (310 nM), SKBR3 (1434 nM), PC3 (210 nM) and HeLa (79 nM) cells with high selectivity. In addition, in silico ADMET properties for the two series were assessed and discussed.

[Hypoxia in cancer malignity. Review]. / Hipoxia en la malignidad del cáncer. Revisión.

Hypoxia is a common characteristic of solid tumors. It contributes to local and systemic tumor progression, as well as the lack of response to radio and chemotherapy, therefore increasing the probability of tumor recurrence. The HIF-1 transcription factor is the main regulator of tumor adaptation to hypoxia stress, stimulating the expression of many genes that allow cells to survive under these conditions. Products dependent on HIF-1 factor are involved in processes of tumor progression, such as proliferation, glucose metabolism, ph-acidosis, angiogenesis and metastasis. It has become increasingly necessary to gain knowledge on the HIF-1 mechanisms of action, since it is possible to find inhibitors that could be used therapeutically against cancer. In this review, a summary is given on the role that the HIF-1 factor plays in hypoxia, as well as its implications on angiogenesis and metastasis.

Identification of dehydroxy isoquine and isotebuquine as promising anticancer agents targeting K+ channel.

Traditional antimalarial drugs based on 4-aminoquinolines have exhibited good antiproliferative activities against human tumor cells; however, their low relative efficacy has limited their corresponding clinical uses. In order to identify new potent anticancer agents based on 4-aminoquinoline, we evaluated the antiproliferative activity of a series of dehydroxy isoquines and isotebuquines against five human cancer lines. HeLa and SKBr3 were significantly more sensitive to the action of tested quinolines than the A549, MCF-7, and PC-3 cancer lines. Compound 2h was by far the most potent derivative against four of the tested lines (except to PC3 line), exhibiting low micromolar or nanomolar IC50 values superior to adriamycin reference, low toxicities on dermis human fibroblasts (LD50  > 250 µM), and excellent selectivity indexes against the mentioned cancer cells. A structure-activity relationship analysis put in evidence that a pyrrolidine or morpholine moiety as N-alkyl terminal substitution and the incorporation of the extra phenyl attached to aniline ring are pharmacophore essentials for improvement the anticancer activity of the studied dehydroxy isoquines and isotebuquines. From the results, compound 2h emerged as a promising anticancer candidate for further in vitro assays against resistant-strain and in vivo studies as well as pharmacokinetic and genotoxicity studies. Mechanistic assays suggested that the most active quinoline 2h act as calcium-activated potassium channel activator.

Cytotoxic and apoptosis-inducing effect of ent-15-oxo-kaur-16-en-19-oic acid, a derivative of grandiflorolic acid from Espeletia schultzii.

ent-Kaurenic acid and many natural derivatives of this diterpene are known to have interesting biological properties. ent-15-Oxo-kaur-16-en-19-oic acid can be easily obtained from grandiflorolic acid which was first isolated from Espeletia grandiflora. The present work describes the proapoptotic effect of ent-15-oxo-kaur-16-en-19-oic acid on the human prostate carcinoma epithelial cell line PC-3 as evidenced by the changes in the expression level of proteins associated with the execution and regulation of apoptosis. Cell viability was affected upon exposure to the compound, the IC(50) were determined as 3.7 microg/ml, which is 4 times lower than that corresponding to a primary cell culture of fibroblasts (14.8 microg/mL). Through Western blot analysis, active forms of caspace-3 associated with the specific proteolysis of Poly(ADP-ribose) polymerase (PARP) were detected. Reduced levels of the antiapoptotic protein Bcl-2, as well as the appearance of internucleosomal DNA fragmentation, were also demonstrated. Thus, ent-15-oxo-kaur-16-en-19-oic acid may be a promising lead compound for new chemopreventive strategies, alone or in combination with traditional chemotherapy agents to overcome drug resistance in tumoral cells.

In vitro 4-Aryloxy-7-chloroquinoline derivatives are effective in mono- and combined therapy against Leishmania donovani and induce mitocondrial membrane potential disruption.

The present study evaluates in vitro the effect of two synthetic compounds of the 7-chloro-4-aryloxyquinoline series, QI (C17H12ClNO3) and QII (C18H15ClN4O2S), on Leishmania donovani parasites. The results obtained demonstrate that these compounds are able to inhibit the proliferation of L. donovani promastigotes in a dose-dependent way (QI IC50 = 13.03 ±â€¯3.4 and QII IC50 = 7.90 ±â€¯0.6 µM). Likewise, these compounds significantly reduced the percentage of macrophage infection by amastigotesand the number of amastigotes within macrophage phagolysosomes, the clinical relevant phase of these parasites. Compound QI showed an IC50 value of 0.66 ±â€¯0.2 µM, while for derivative QII, the corresponding IC50 was 1.02 ±â€¯0.17 µM. Interestingly, the amastigotes were more susceptible to the drug treatment when compared to promastigotes. Furthermore, no cytotoxic effect of these compounds was observed on the macrophage cell line at the concentrations tested. The combination of these compounds with miltefosine and amphotericin B on both parasite morphotypes was evaluated. The isobolograms showed a synergistic effect for both combinations; with a Fractional Inhibitory Concentration (FIC) Index lower than 1 for promastigotes and less than 0.3 for intracellular amastigotes. The effect of QI and QII on mitochondrial membrane potential was also studied. The combination of quinolone derivatives compounds with miltefosine and amphotericin B showed 5-8-fold stronger depolarization of membrane mitochondrial potential when compared to drugs alone. The present work validates the combination of drugs as an effective alternative to potentiate the action of anti-Leishmania agents and points to the quinoline compounds studied here as possible leishmanicidal drugs.

[Tissue engineering and construction of human skin in vitro]. / Ingeniería de tejidos y producción de piel humana in vitro.

Tissue engineering is the new science that has come to make possible the growth of new organ tissue from small fragments of healthy tissue, thus partially or totally restoring the lost functions of ill tissues or organs, as shown by the achievements made with the culture of skin, cornea or cartilage. Thus far, this new science is able to ensure the recovery of lost functions and, doubtlessly, in a near future will be capable of developing tissues and organs not unlike natural ones. In our laboratory we have began the development of tissue engineering techniques for the successful construction of in vitro skin with the aim at mid term of producing cornea and cartilage. In a first clinical trial, these techniques were applied in the treatment of chronic skin lesions and the advantages and reach of these new tools were demonstrated for the effective solution of problems with would otherwise not be easily solved through the use of conventional treatments.

Effect of tetrahydroquinoline derivatives on the intracellular Ca2+ homeostasis in breast cancer cells (MCF-7) and its relationship with apoptosis / Efecto de derivados de tetrahidroquinolinas sobre la homeostasis del Ca2+ intracelular en células de cáncer de mama (MCF-7) y su relación con la apoptosis

Abstract Tetrahydroquinoline derivatives are interesting structures exhibiting a wide range of biological activities, including antitumor effects. In this investigation, the effect of the synthesized tetrahydroquinolines JS-56 and JS-92 on apoptosis, intracellular Ca2+ concentration ([Ca2+]i), and the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity was determined on MCF-7 breast cancer cells. Colorimetric assays were used to assess MCF-7 cells viability and SERCA activity. Fura-2 and rhodamine 123 were used to measure the intracellular Ca2+ concentration and the mitochondrial electrochemical potential, respec tively. TUNEL assay was used to analyze DNA fragmentation, while caspase activity and NF-κB-dependent gene expression were assessed by luminescence. In silico models were used for molecular docking analysis. These compounds increase intracellular Ca2+ concentration; the main contribution is the Ca2+ entry from the extracellular milieu. Both JS-56 and JS-92 inhibit the activity of SERCA and dissipate the mitochondrial electrochemical potential through processes dependent and independent of the Ca2+ uptake by this organelle. Furthermore, JS-56 and JS-92 generate cytotoxicity in MCF-7 cells. The effect of JS-92 is higher than JS-56. Both compounds activate caspases 7 and 9, cause DNA fragmentation, and potentiate the effect of phorbol 12-myristate-13-acetate on NF-κB-dependent gene expression. Molecular docking analysis suggests that both compounds have a high interaction for SERCA, similar to thapsigargin. Both tetrahydroquinoline derivatives induced cell death through a combination of apoptotic events, increase [Ca2+]i, and inhibit SERCA activity by direct interaction.

Resumen Los derivados de tetrahidroquinolina son estructuras interesantes que exhiben una amplia gama de actividades biológicas, incluyendo efectos antitumorales. Se determinó el efecto de las tetrahidroquinolinas sintetizadas JS-56 y JS-92 sobre la apoptosis, concentración intracelular de Ca2+ ([Ca2+]i) y la actividad Ca2+-ATPasa del retículo sarco(endo)plásmico (SERCA) en células de cáncer de mama MCF-7. Se usaron ensayos colorimétricos para evaluar la viabilidad de las células MCF-7 y la actividad SERCA. Se emplearon Fura-2 y rodamina 123 para medir la concentración de Ca2+ intracelular y el potencial electroquímico mitocondrial, respectivamente. El ensayo TUNEL se utilizó para analizar la fragmentación del ADN, mientras que la actividad de caspasas y la expresión génica dependiente de NF-κB se evaluaron mediante luminiscencia. Modelos in silico permitieron el análisis del acoplamiento molecular. Estos compuestos aumentan la concentración de Ca2+ intracelular; la principal contribución es la entrada de Ca2+ desde el medio extracelular. Tanto JS-56 como JS-92 inhiben la actividad de SERCA y disipan el potencial electroquímico mitocondrial a través de procesos dependientes e independientes de la captación de Ca2+ por este orgánulo. Además, JS-56 y JS-92 generan citotoxicidad en células MCF-7. El efecto de JS-92 es mayor que JS-56. Ambos compuestos activan las caspasas 7 y 9, provocan la fragmentación del ADN y potencian el efecto del 12-miristato-13-acetato de forbol en la expresión génica dependiente de NF-κB. El análisis de acoplamiento molecular sugiere que ambos compuestos tienen una alta interacción con SERCA, similar a la tapsigargina. Ambos derivados de tetrahidroquinolina indujeron la muerte celular a través de una combinación de eventos apoptóticos, aumento de [Ca2+]i e inhibición de la actividad SERCA por interacción directa.

[Metalloproteinases in tumor progression. Review]. / Metaloproteasas en la progresión tumoral. Revisión.

The two biological characteristics that determine the malignancy of cancer are infiltration and metastasis. The study of these mechanisms is related to the invasion of tumoral cells and the relationship of these cells with their stroma, which interact producing the movement and accumulation of inflammatory cells, the formation of new blood vessels, multiplication of fibroblasts and the synthesis of the components of the extra cellular matrix production. Tumoral invasion is conditioned through various enzyme activities, in particular proteases which degrade the matrix, thus facilitating the progression of the tumor. The metalloproteinases (MMP) are a family of proteinases that play an important role in cancer as well as in numerous other diseases. MMP are, therefore, a potential factor in cancer therapy. Several synthetic MMP inhibitors have been developed and have shown successful anti-tumor activity in a variety of animal species, but in clinical studies of patients with advanced forms of cancer, this therapeutic strategy has not resulted as effective. In this article, due to the biological and clinical importance of this therapy, we summarize the current views on the role of metalloproteinases (MMP) in tumor promotion, proliferation, invasion, metastasis and angiogenesis.

Cancer and the metastatic substrate.

Seventy percent of cancer patients have detectable metastases when they receive a diagnosis and 90% of cancer deaths result from metastases. These two facts emphasise the urgency for research to study the mechanisms and processes that enable metastasis. We need to develop a greater understanding of the cellular and molecular mechanisms that cause metastasis and also we need to do more. We must also consider the micro- and macro-environmental factors that influence this disease. Studying this environmental context has led us to update the 'seed and soil' hypothesis which dates back to the 19th century. This theory describes cancerous cells as seeds and the substrate as the soil in target organs though this may seem antiquated. Nonetheless, the tissue specificity that researchers have recently observed in metastatic colonisation supports the validity of the seed and soil theory. We now know that the metastatic potential of a tumour cell depends on multiple, reciprocal interactions between the primary tumour and distant sites. These interactions determine tumour progression. Studies of metastasis have allowed us to develop treatments that focus on therapeutic effectiveness. These new treatments account for the frequent metastasis of some tumours to target organs such as bones, lungs, brain, and liver. The purpose of this review is first to describe interactions between the cellular and molecular entities and the target organ tumour environment that enables metastasis. A second aim is to describe the complex mechanisms that mediate these interactions.

Tumour progression and metastasis.

The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour's survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible.