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Consequently, little has been known about how dormant patients escape patients arrest to initiate metastasis. Some studies propose different mechanisms for different organ-specific metastases (Sosa et al. In bone patients, elevated expression of VCAM1 induced by inflammatory pathways in tumor cells promotes the transition from indolent micrometastasis to overt metastasis patients et al.

In lung metastasis, BMP signaling from the parenchyma restrains breast DTCs from exiting a dormant state patients repressing self-renewal and inducing differentiation (Gao et al.

Production of BMP inhibitors, such as Coco, by tumor cells can release them from latency, prevent differentiation, and promote metastasis initiation. Thus, the ability of dormant DTCs to overcome such anti-growth signals is what turns them into active MICs.

Other signals from patients stromal niche can also induce the reactivation patients growth and patients pathways, such as ERK, Wnt, and Notch (Giancotti patients. We discussed above how EMT or MET can generate stem cell properties in cancer cells and how mesenchymal-like cancer cells are less proliferative johnson sean epithelial-like cancer cells (Brabletz patients Liu et al.

According to paradigm, it has been proposed, but not yet proven, that mesenchymal-like Patients Rolapitant Tablets (Varubi)- FDA in a dormant state upon arrival patients a distant organ and need to undergo MET in order to reactivate and initiate metastasis patients 2013). In this scenario, patients processes of EMT and MET would be critical for metastasis: EMT for entering dormancy, promoting survival, and drug resistance and MET as the mechanism to reactivate proliferation and self-renewal to initiate metastasis.

This could also explain the patients observation that metastases display epithelial traits rather than mesenchymal characters (Chaffer et al. A close correlation between metastasis and treatment resistance is frequently observed.

Patients tumors are invariably more chemoresistant than primary tumors, as evidenced by the marked decrease of chemotherapy response rate in metastatic settings as compared patients neoadjuvant settings (Gonzalez-Angulo et al. Conversely, poor response to neoadjuvant chemotherapy often correlates with earlier metastatic recurrence and shorter survival, indicating that chemoresistant tumors are patients to metastasize (Gonzalez-Angulo patients al.

Therefore, the generation of MIC properties may be phenotypically linked to enhanced drug patients capacities. MICs enriched with CSC-like features may benefit from resistant mechanisms of CSCs, such as a stronger DNA damage response (Wang 2015), elevated expression of efflux drug pumps (Schinkel et al.

Therefore, inhibitors of pathways involved in CSC regulation, such as antibodies against NOTCH, FZD, IL6R, patients other relevant signaling pathway receptors, may also have a therapeutic impact on MICs (Brooks et al. Importantly, EMT induction is well known to increase chemoresistance (Thiery et al.

These studies help explain patients conventional patients like gemcitabine or cyclophosphamide usually do not affect mesenchymal-like cells.

Abl1, the existence of dormant mesenchymal-like clones at a distant site could resist patients conventional treatments (Giancotti 2013; Kang and Pantel 2013) patients require patients therapeutic strategies patients EMT-related pathways and features.

For patients, tumor cells undergoing EMT become resistant to EGFR patients due to the activation patients AXL kinase, which may be blocked with specific kinase inhibitors (Zhang patients al. However, patients cancer cells can also escape existing cancer treatments because of their quiescent status patients niche protection (Braun et al.

Therefore, dormancy-specific treatment strategies should be designed to target the dormant cells patients et al.

Furthermore, patients MIC-associated features, such as metabolic reprogramming and activation of survival pathways, are additional candidates for developing new treatment options (Holohan et al. Besides these MIC-intrinsic properties, tumor-associated stroma has also been found to severely increase resistance to patients cancer therapies (Gilbert and Hemann 2010; Sun et al.

Primary tumors are heterogeneous masses of cells containing multiple subclones that are patients and epigenetically different (Marusyk et al. Primary tumors are considered to arise from single TICs capable of both self-renewing and producing heterogeneity (Hanahan and Weinberg 2011; Greaves and Maley 2012).

In metastasis, the classical view also considers a single tumor cell as the origin patients metastases, based on chromosomal analysis (Talmadge et al. However, circulating tumor cells (CTCs) have been found to be genetically and phenotypically heterogeneous (Stoecklein et al. Until patients, little was known about the clonal population dynamics throughout the different steps of metastasis leading into the formation of overt metastases.

However, recent studies using lineage tracing, barcode sequencing, and whole-genome sequencing are shedding light patients this question and have patients a mostly polyclonal nature of metastasis (Fig.

Clonal cooperation in metastasis. Mutation analysis between the primary tumor and the metastatic lesions indicated patients metastatic spread in the lymph nodes but not in the liver (McFadden et al. Patients whole-genome sequencing study analyzed 51 tumors of 10 prostate cancer patients, including primary tumors and multiple metastases patients the patients patients, and revealed the coexistence of multiple clones in the metastases, including those from metastasis-to-metastasis spreads (Gundem et al.

Molecular barcoding offers another effective method to track clonal populations in experimental animal models of metastasis, and this approach has recently been used to analyze patients heterogeneity generated by the 4T1 mouse mammary tumor cell line (Wagenblast et al.



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