Considering the pleiotropic role of annexin A2 in cancer progression, we speculate that the novel LOXL4-mediated mechanism identified herein (i.e., a LOXL4-annexin A2-integrin α6/integrin β-1 axis) plus the already reported multiple means of annexin A2 are exerted together simultaneously or separately in not only specific cellular contexts such as proliferation, the EMT, migrative invasion, survival, and adhesion, but also cancer extracellular milieus such as matrices’ remodeling, angiogenesis, and macrophage-mediated immune tolerance, through the processes of cancer metastatic progression. The gene discussed is TWF1; the disease is cancer.