**6. Remodeling of normal tissue to TME**

In the next three pictures, we visualize the remodeling process from "normal" ECM of the normal state of the rectum to the appearance of the tumor microenvironment (TME), with two well-defined parts: the proliferative well-vascularized peripheral one and a central necrotic part (in the middle). Six weeks after neoadjuvant radio-chemotherapy, a partial remission with a complete disappearance of the well-vascularized macroscopic part of the tumor was reached (right) and a remnant scar at the site of the necrotic part of the treated primary rectal cancer was noted.

The representation of the complex process from a normal rectal mucosa state (left picture) to the state in which rectal cancer with its central necrotic part and the peripheral well-vascularized part (in the middle), under neoadjuvant radio-chemotherapy was reduced to scar tissue (right picture) is shown in **Figure 4**. This is the visualized tumor response after 56 Gy was applied in 28 fractions on the macroscopic visible tumor (in the middle). The histologic examination of the scar revealed only remnant tumor cells in the lymphatics (LVI). One year later, the patient developed multiple brain metastases.

#### **Figure 4.**

*Normal rectal mucosa before tumor appearance (left), with macroscopic tumor (middle) and 6 weeks after radio-chemotherapy (right) and before surgery.*

#### **Figure 5.**

*Schematic representation of the ECM in normal tissue (left), TME in tumor tissue (middle), and ECM modified after radiation therapy (right) [1].*

Above is a schematic representation of the ECM at the level of the normal rectum (left side), of the tumor microenvironment (TME) of the rectal tumor (in the middle), and the "remodeled" TME with the complete destruction of the tumor now "remodeled ECM" and a recovered basal membrane (right side) (**Figure 5**).

The "Remodeled" ECM after treatment became more abundant, denser, stiffer, with more fibroblasts and collagen.
