Proapoptotic tumor suppressor WWOX is upregulated in the early stage of cancer initiation, which probably provides limitation to cancer growth and progression. Later, WWOX protein is reduced to enhance cancer cell growth, migration, invasiveness and metastasis. To understand how WWOX works in controlling cancer progression, here we demonstrate that apoptotic stress mediated by ectopic WWOX stimulated cancer cells to secrete basic fibroblast growth factor (bFGF) in order to support capillary microtubule formation. This event may occur in the cancer initiation stage. Later, when WWOX loss occurs in cancer cells, hyaluronidase production is then increased in the cancer cells to facilitate metastasis. We determined that inhibition of membrane hyaluronidase Tyr216-phosphorylated Hyal-2 by antibody suppresses cancer growth in vivo. WWOX-negative (WWOX-) cells dodged WWOX+cells in the microenvironment by migrating individually backward to avoid physical contacts and yet significantly upregulating the redox activity of WWOX+parental cells or other WWOX+cell types for causing apoptosis. Upon detecting the presence of WWOX+cells from a distance, WWOX- cells exhibit activation of MIF, Hyal-2, Eph, and Wnt pathways, which converges to MEK/ERK signaling and enables WWOX- cells to evade WWOX+cells. Inhibition of each pathway by antibody or specific chemicals enables WWOX- cells to merge with WWOX+cells. In addition, exogenous TGF-β assists WWOX- cells to migrate collectively forward and merge with WWOX+cells. Metastatic WWOX- cancer cells frequently secrete high levels of TGF-β, which conceivably assists them to merge with WWOX+cells in target organs and secure a new home base in the WWOX+microenvironment. Together, loss of WWOX allows cancer cells to develop strategies to dodge, compromise and even kill WWOX-positive cells in microenvironment.

促凋亡的肿瘤抑制因子WWOX在癌症发生的早期阶段被上调，这可能限制了癌症的生长和发展。后来，WWOX蛋白被还原以增强癌细胞的生长，迁移，侵袭性和转移。为了了解WWOX如何控制癌症进展，在这里我们证明由异位WWOX介导的凋亡应激刺激癌细胞分泌碱性成纤维细胞生长因子（bFGF），以支持毛细血管微管的形成。此事件可能发生在癌症的起始阶段。后来，当癌细胞中发生WWOX丢失时，癌细胞中透明质酸酶的产量就会增加，以促进转移。我们确定抗体对膜透明质酸酶Tyr216磷酸化的Hyal-2的抑制作用抑制了体内癌症的生长。WWOX阴性（WWOX-）细胞通过向后个别迁移以避免物理接触，而在微环境中避开WWOX +细胞，但仍显着上调WWOX +亲代细胞或其他WWOX +细胞类型的氧化还原活性，从而导致细胞凋亡。在远距离检测到WWOX +细胞的存在后，WWOX-细胞表现出MIF，Hyal-2，Eph和Wnt途径的激活，这些途径收敛于MEK / ERK信号传导，并使WWOX-细胞逃避WWOX +细胞。抗体或特定化学物质对每种途径的抑制作用使WWOX-细胞与WWOX +细胞融合。另外，外源性TGF-β辅助WWOX-细胞共同向前迁移并与WWOX +细胞融合。转移性WWOX-癌细胞经常分泌高水平的TGF-β，可以想象，这有助于它们与目标器官中的WWOX +细胞融合，并在WWOX +微环境中获得新的家庭基地。在一起，WWOX的丢失使癌细胞能够制定策略来躲避，损害甚至杀死微环境中的WWOX阳性细胞。