**Abstract**

Remodeling is a new concept used to describe the effects of cancer cells properties to modify the extracellular microenvironment (ECM) to favor the proliferation, invasiveness, migration, and metastatic potential of the tumor. All these characteristics are determined by both the direct and indirect interactions of the cancer cells, with components of their microenvironment. The remodeling concept described in this chapter considers the changes produced by the local treatment alone, or in combination with systemic treatments on local advanced primary tumors or bone metastases (vertebral body or pelvic bones). The cases presented considered locally advanced cancer that disturbed the local anatomy at different levels as chest wall, the skin of the face, eye orbit, and vertebral or pelvic bones. Changes in the extracellular microenvironment, after the applied treatment, normalized all or only in special parts of the extracellular matrix, with a remodeling organ-specific process to the treated tumor bed. In some of these cases was reached a restitutio till to the most important component, the basal membrane. The four phases of the healing process of lesions produced by radiotherapy (the hemostasis, inflammatory, proliferative, and remodeling phase) and the possible changes at the level of ECM were here analyzed.

**Keywords:** remodeling, radiotherapy, extracellular microenvironment, locally advanced cancer, restitutio ad integrum, healing process

### **1. Introduction**

There has been a massive shift in our approach to understand the biology of solid tumors in the last decades. While research centered for a long time nearly exclusively on the individual tumor cells, the process leading to their transformation, or conveying their malignancy, and the tumor as a complex organ, meanwhile the term tumor microenvironment (TME) is used, to describe the entirety of the tumor components that are not malignant by themselves. Thus, the TME consists of the tumor vasculature, connective tissue, infiltrating immune cells, and the extracellular matrix (ECM). Increasingly, all these individual components of the TME became the focus of new research communities within the fast-growing cancer field. The ECM is probably the component of the TME that initially received the least attention, but this also changed considerably over the last decade. The numerous articles have, bit by bit, complemented our understanding of the tumor ECM and its role in malignancy and response to therapy [1].

Cancer represents a dysregulation of the body's normal, controlled cellular programs. Malignant cells are able to confer enhanced proliferation, resistance to apoptosis, or motility that allows tumors to metastasize (colonize) the distant

#### *Radiation Oncology*

organs, which is the most lethal aspect of cancer. Tumor cells also require the collaboration of the tumor microenvironment (TME) for growth and progression [2].

Tumor hypoxia or increased inflammation in the TME modifies tumor ECM components and increases collagen deposition, ECM density, and stiffness. In addition, it is known that adhesion to the dense ECM modifies the radiation sensitivity of cancer cells.

Radiotherapy is considered as one of the potentially curative modalities for cancer. The tumor ECM might play a pivotal role in resistance and recurrences to radiotherapy in different cancers.

### **2. Remodeling as part of cancer development**

Recent concepts of ECM remodeling shaping tissues for tumor cells to invade and metastasize during cancer development are discussed in the literature. Increasing understanding of these processes opens up the possibilities of therapeutic approaches to target the aberrant ECM and/or the underlying pathologic mechanisms of its remodeling and prevent malignancy. Changing single elements can turn over the delicate balance of ECM remodeling events.

It is not surprising that cancer cells modify all four ECM remodeling mechanisms, creating a cancer-supporting matrix that actively contributes to the pathology of the tumor.

The tumor microenvironment regulates cancer initiation, progression, and response to therapy. The immature tumor vasculature may impede drugs from reaching tumor cells at a lethal concentration. Potiron et al. [3] have shown that RT-induced vascular remodeling translates into improved tissue distribution and efficacy of chemotherapy.

Radiotherapy (RT) induces vascular remodeling, accompanied by decreased hypoxia and/or increased perfusion. In a low dose regime (2 Gy/fraction) it is a common effect. Intra-tumoral doxorubicin distribution was improved.

These data demonstrate that RT favors the efficacy of chemotherapy by improving tissue distribution and could be an alternative chemo sensitization strategy.

Even in the era of targeted therapies, the limited distribution of drugs remains a challenge. This is part of the abnormal tumor vasculature, which has developed as a function of anarchic tumor expansion. The resulting network is tortuous, overbranched, variable in diameter, and abnormally permeable [3]. The consequence is reduced blood flow. Additional tumor cell density creates a compressive environment that blunts the endothelial lumen and limits the extravasation of molecules because of high interstitial pressure. The abnormal vasculature generates hypoxia and acidosis, leading to metabolism switch and the emergence of therapeutic resistance. Moreover, destructing angiogenesis or altering vascular maturation could favor metastasis.

External radiotherapy is today a standard treatment for about half of cancer patients, either alone or in combination with surgery and/or chemotherapy, given in a fractionated regimen of about 2 Gy/day, over a course of several weeks, to achieve a total dose of 32–80 Gy, depending on tumor type and location. Endothelial deaths after irradiation might be trigger only above 5–10 Gy.

Ultimately, RT leads to the destruction of target tissues. However, this process is gradual and allows time for complex biological phenomena to occur. Potiron et al. [3] have shown in a xenograft prostate model that RT induces perivascular coverage of tumor micro-vessels.

Pericytes belong to a versatile cell population, whose function and origin are still under debate. Their interaction with endothelial cells is dynamic during vascular

development and maturation. The lack of pericytes impairs vascular function and favors metastasis. Whether pericytes contribute to upregulating perfusion in a radiotherapy context is not completely elucidated. The function of pericytes in regulating blood flow is currently questioned [3].
