**2. Invasion and metastatic skills**

The dissemination of tumors is a complex process occurring in a sequential series which can be named as a sequence of invasive‐metastatic events (**Figure 1**). These phases are composed

**Figure 1.** Abnormal ECM promotes cancer progression. (A) ECM remodeling is tightly controlled to ensure organ ho‐ meostasis and functions. Normal ECM dynamics are essential for maintaining tissue integrity and keep rare tumor‐ prone cells, together with resident fibroblasts, eosinophils, macrophages, and other stromal cells, in check by maintaining an overall healthy microenvironment. (B) With age or under pathological conditions, tissues can enter a series of tumorigenic events. One of the earlier events is the generation of activated fibroblasts or CAFs (stage 1), which contributes to abnormal ECM buildup and deregulated expression of ECM remodeling enzymes (stage 2). Ab‐ normal ECM has profound impacts on surrounding cells, including epithelial, endothelial, and immune cells and other stromal cell types. Deregulated ECM promotes epithelial cellular transformation and hyperplasia (stage 3). (C) In late‐ stage tumors, immune cells are often recruited to the tumor site to promote cancer progression (stage 4). In addition, deregulated ECM affects various aspects of vascular biology and promotes tumor‐associated angiogenesis (stage 5). Creation of a leaky tumor vasculature in turn facilitates tumor cell invasion and metastasis to distant sites (stage 6). (D) At distant sites, cancer cells leave the circulation and take hold of the local tissue. Together with local stromal cells, cancer cells express ECM remodeling enzymes and create a local metastatic niche. Abnormal niche ECM promotes ex‐ travasation, survival, and proliferation of cancer cells (stage 7). At later stages when cancer cells awake from dorman‐ cy, abnormal ECM turns on the angiogenic switch (stage 8), presumably using a mechanism similar to that used at the primary site (stage 5), and promotes the rapid growth of cancer cells and an expansion of micrometastasis to macrome‐ tastasis (see ref. [5]).

of local invasion, entry into blood and lymphatic vessels (intravasation), intravenous journey, exit from the veins (extravasation), development of micrometastases, and finally the growth of the micrometastases into macroscopic tumors [18, 19]. As it might be expected, any one of these phases may be interrupted by factors associated with the tumor or host. The series of metastatic events may also be divided into two phases, namely (1) ECM invasion and (2) intravenous dissemination of tumor cells and their homing in distant tissues/organs [20].
