The Biology of Skin Cancer Invasion and Metastasis

Introduction

According to National Cancer Institute estimates, more than one million cases of cutaneous malignancies were diagnosed in 2009 in the United States (US) with basal cell carcinoma representing the vast majority of cases (80–90%). Other estimates suggest that the number of cases in the US exceeds 3 million annually. While incidence rates for most major cancers in the US are falling, that the rate of melanoma continues to rise is of utmost concern, considering that the 5-year survival rate for patients with metastatic melanoma is less than 10%.

Deaths from cutaneous malignancies are most often due to recurrent metastases that are chemoresistant and unrelenting. While metastatic potential is far from equal across the three major neoplasms, their relatively high and rising (in the case of melanoma) incidence should put consideration and evaluation for metastasis on the checklist of all healthcare providers as they diagnose and treat each patient.

In particular, the resistance of metastatic melanoma to conventional therapy can be attributed to the biologic heterogeneity present not only in the primary tumor but in subsequent metastatic foci as well. The once dominant perception that neoplasms are nothing more than monoclonal, homogenous collections of cells characterized predominantly by unregulated growth has been replaced by a seemingly more sinister and complex understanding.

What is now readily apparent is that tumors are collections of many distinct cell populations with varied growth rates, metastatic potentials, karyotypes, immunogenicities, and treatment sensitivities; the inherent genomic instability accounts for the variation in capacities, and a fully capable metastatic cell is actually a rare clone within a larger tumor. Moreover, stromal microenvironments surrounding the primary tumor and its end-organ metastatic targets also play critical roles in the acceptance, maintenance and propagation of these unique cell types. Resistance to current therapeutic modalities is most likely due to the aggregate of myriad cell types and stromal milieus.

Only continued investigation into the mechanisms underlying the development and sustainability of this phenomenon will permit the breakthroughs necessary for the ultimate treatment strategy to emerge.

Mechanisms of cancer growth and metastasis

The process of cancer metastasis is dynamic, complex and consists of a large series of interrelated steps. While the complete picture is yet to emerge, a growing narrative demonstrates consistent principles and conditions absolutely necessary for invasion and metastasis across all cancer types. To produce a clinically relevant lesion, metastatic cells must survive all the steps of the process. If a cell or subset of cells fails to develop any one of these ‘steps’ and/or the surrounding microenvironment is inhospitable, it is rendered impotent and cannot successfully propagate outside of the primary tumor site.

In essence, cellular aggregates capable of metastasis are selected for through a series of rigorous and stringent conditions that may not be present entirely throughout the tumor or the target organ but at specific locations within them. A general scheme for metastatic selection can be thought of as a process that follows the following order ( Figs 1.1 and 1.2 ):

• 1.

  Initial transformation and propagation

• 2.

  Neoplastic angiogenesis and lymphangiogenesis

• 3.

  Local extension

• 4.

  Entry into venolymphatic channels

• 5.

  Detachment and embolization of tumor cell aggregates

• 6.

  Immune system evasion and survival in the general circulation

• 7.

  Arrest in capillary or lymphatic beds

• 8.

  Extravasation into secondary target sites

• 9.

  Proliferation within secondary target sites