More and more evidences have shown that the development and metastasis of tumors rely on the support of micro-environments around them. The constitution of micro-environment include the collagen, vessels, immune cells, and resident cells. In order to work out the strategies for cancer treatment, we need to understand the underlying dynamics and interaction among those critical factors. The critical patho-physiology may involve the collagen remodeling, hypoxia, angiogenesis, tumor associate macrophages etc. Here in our lab, we use melanoma as a model to study the collagen remodeling in vivo. Without sacrificing the mice, we can track the collagen remodeling with harmonic generation microscopy (HGM) on the same mice along the development of tumors. Using quantitative imaging analysis on those HGM images , we found significant changes at early stages. These indices can serve as quantitative measure for virtual optical biopsies to diagnose cancer conditions in vivo.