Accumulated reports showed that spheroid culture mimics the cancer environment better than a 2D culture in terms of cell-cell contacts, drug resistance, drug penetration, and nutrient efficiency [23], [29]; therefore, the functions of endogenously expressed proHB-EGF found in the 3D spheroid suggest that proHB-EGF may play important roles in tumor progression. Here, P4HB is linked to neoplasm.