Metastasis

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• Scientists are still trying to understand the biological basis underlying the dissemination and outgrowth of tumor cells, why these cells can remain dormant for years, how they become resistant to the immune system or cytotoxic effects of systemic therapy, and how they interact with their new microenvironment.

• One opportunity involves therapies targeting premetastatic niches (PMNs), defined as those inflamed distant environments rendered favorable to supporting tumor metastasis under the influence of tumor-secreted soluble factors and tumor-shed extracellular vesicles (EVs).

• The hallmark of the PMN is the co-existence of multiple pathological changes even prior to the arrival of metastatic tumor cells.

• Mounting clinical evidence documents the presence of PMNs in cancer patients, in lymph nodes as well as in distant tissues such as the omentum and liver

• The detection of PMNs will require synergistic approaches combining new imaging tools, such as SPECT/PET and ultrahigh magnetic field MRI, biopsies of lymph nodes and distant organs, and examination of tumor-secreted biomarkers, such as tissue and plasma-derived EV proteins, DNA, and RNA.

• the perivascular niche also drives therapeutic resistance.

• dormant cells have a unique metabolism.

• The key is understanding how disseminated tumor cells influence their microenvironment and how the niche responds in kind.

• For these reasons, I’m tremendously optimistic that dormancy will shift from a biological fascination to a clinical target much sooner than later.

• patients with cancer can spend years (or even decades) free of symptomatic disease before metastases emerge.

• lingering disseminated tumor cells (DTCs) that found residency at distant sites under a state of dormancy

• Harnessing this enormous potential for intervention requires discovering how DTCs become dormant, what causes them to awaken, and how dormant DTCs can be targeted.

• blocking integrin-mediated adhesions between DTCs and the perivasculature sensitizes dormant DTCs to chemotherapy.

• Another prospect is the use of adjuvant natural killer cell immunotherapy to maintain long-term dormancy

• crosstalk in response to individual’s exposures, such as aging, inflammation, and lifestyle choices

• detection of even a single DCC is associated with higher relapse risk

• DCCs carrying driver mutations can spontaneously or in response to therapies (persisters) pause progression and undergo a process globally defined as dormancy

• Sequencing studies of “normal” tissues revealed abundant driver mutations that do not manifest until the tissue niches or systemic alterations (e.g., inflammation, aging) perturb homeostasis

• It appears that dormant DCCs can also fit in this model where microenvironment-driven epigenetic changes override genetic driver function.

• epigenetic drugs like azacytidine and retinoic acid, and small-molecule agonists of NR2F1, induce dormancy programs and suppress metastasis.