The cell surface hyaluronan receptor CD44 promotes tumor growth and metastasis by mechanisms that remain poorly understood. We show here that CD44 associates with a proteolytic form of the matrix metalloproteinase-9 (MMP-9) on the surface of mouse mammary carcinoma and human melanoma cells. CD44-associated cell surface MMP-9 promotes cell-mediated collagen IV degradation in vitro and mediates tumor cell invasion of G8 myoblast monolayers. Several distinct CD44 isoforms coprecipitate with MMP-9 and CD44/MMP-9 coclustering is observed to be dependent on the ability of CD44 to form hyaluronan-induced aggregates. Disruption of CD44/MMP-9 cluster formation, by overexpression of soluble or truncated cell surface CD44, is shown to inhibit tumor invasiveness in vivo. Our observations indicate that CD44 serves to anchor MMP-9 on the cell surface and define a mechanism for CD44-mediated tumor invasion.

To confirm the relationship between sex and the progression of Coronavirus , and its potential mechanism, among severe patients. For this retrospective study, we included 168 consecutive severe patients with pathogen-confirmed COVID-19 who were hospitalized between January 16th and February 4th, 2020, at Tongji Hospital in Wuhan, China. Clinical characteristics, laboratory parameters, and outcomes were compared and analyzed between males and females. In the present study, we analyzed 168 severe patients with COVID-19, including 86 males and 82 females, and 48 patients (28.6%) were diagnosed as critically ill. Of 86 male patients, 12.8% (11/86) died and 75.6% (65/86) were discharged; of 82 female patients, 7.3% (6/82) died and 86.6% (71/82) were discharged. Eleven laboratory parameters showed significant differences between male and female patients, and six of them were higher during the whole clinical course in patients who died than in patients who were discharged. In adjusted logistic regression analysis, males with comorbidities presented a higher risk of being critically ill than males without comorbidities (OR = 3.824, 95% CI = 1.279-11.435). However, this association attenuated to null in female patients (OR = 2.992, 95% CI = 0.937-9.558). A similar sex-specific trend was observed in the relation between age and critically ill conditions. We highlighted sexspecific differences in clinical characteristics and prognosis. Male patients appeared to be more susceptible to age and comorbidities. Sex is an important biological variable that should be considered in the prevention and treatment of COVID-19. PLOS PATHOGENSPLOS Pathogens | https://doi.

To understand how the hyaluronan receptor CD44 regulates tumor metastasis, the murine mammary carcinoma TA3/St, which constitutively expresses cell surface CD44, was transfected with cDNAs encoding soluble isoforms of CD44 and the transfectants (TA3sCD44) were compared with parental cells (transfected with expression vector only) for growth in vivo and in vitro. Local release of soluble CD44 by the transfectants inhibited the ability of endogenous cell surface CD44 to bind and internalize hyaluronan and to mediate TA3 cell invasion of hyaluronan-producing cell monolayers. Mice intravenously injected with parental TA3/St cells developed massive pulmonary metastases within 21–28 d, whereas animals injected with TA3sCD44 cells developed few or no tumors. Tracing of labeled parental and transfectant tumor cells revealed that both cell types initially adhered to pulmonary endothelium and penetrated the interstitial stroma. However, although parental cells were dividing and forming clusters within lung tissue 48 h following injection, >80% of TA3sCD44 cells underwent apoptosis. Although sCD44 transfectants displayed a marked reduction in their ability to internalize and degrade hyaluronan, they elicited abundant local hyaluronan production within invaded lung tissue, comparable to that induced by parental cells. These observations provide direct evidence that cell surface CD44 function promotes tumor cell survival in invaded tissue and that its suppression can induce apoptosis of the invading tumor cells, possibly as a result of impairing their ability to penetrate the host tissue hyaluronan barrier.