Characteristics, such as sustained proliferation, circumventing growth suppression, evading destruction by immune cells, enabling replicative immortality, inducing angiogenesis and resisting cell death are considered hallmarks of cancer.1 The enhancement of tumorigenesis by oncogenes and release of tumor growth inhibition by tumor suppressor genes together contribute toward cancer progression. In addition, reprogramming of cellular metabolism, caused by alterations in intracellular and extracellular metabolites, can also influence the tumor microenvironment (TME), resulting in tumorigenesis.2
Types of Cancers
Cancer classification is based on the embryological origin of the tissue from which the cancer develops. Types of cancers include carcinoma, sarcoma, hematopoietic (e.g., leukemia, lymphoma, plasma cell neoplasms), central nervous system (CNS) cancers (brain and spinal cord), and germ cell cancers.
Carcinoma
A carcinoma is a cancer that originates from the epithelial cells of the skin or lining of internal organs. Some types of carcinoma include squamous cell carcinoma, adenocarcinoma and hepatocellular carcinoma.3
Sarcoma
A sarcoma is a cancer of mesenchymal origin arising from the supportive or connective tissues. Soft tissue sarcoma and osteosarcoma are the two main categories of sarcoma. Some examples of sarcoma include angiosarcoma of the blood vessels, fibroblastic sarcoma and chondrosarcoma.4
Hematopoietic cancers
Hematopoietic cancers, which include leukemia and lymphoma, derive from hematopoietic cells.
Leukemia is a cancer of white blood cells (WBCs). In leukemia, the hematopoietic progenitors undergo uncontrolled expansion, resulting in an overproduction of WBCs and the inability to produce enough red blood cells and platelets. Based on the maturation of leukemic cells, leukemia is categorized into two types—acute or chronic.5
Lymphoma is a blood cancer affecting the lymphatic system and B and T cell populations of WBCs. Most lymphomas (90%) originate from B cells and the remaining 10% are T and NK cell neoplasms.6
Central nervous system (CNS) cancers
CNS cancers are cancers of the brain and spinal cord that arise from the neural crest. They can be primary CNS cancers or metastatic. Some examples include primary CNS lymphoma (PCNSL), astrocytoma, oligodendroglioma, ependymoma and glioblastoma multiforme (GBM). Glioblastoma is the most common and the most aggressive primary brain tumor in adults. Even with surgical resection, chemotherapy and radiotherapy, GBM has a poor prognosis with a median survival of just over 1 year.7 Different subtypes of GBMs have been described based on the genetic alterations they harbor, such as loss of tumor suppressors (e.g., TP53, CDKN2A, PTEN) or overexpression of oncogenes (e.g., EGFRVIII).
Germ cell cancers
Germ cell neoplasia in situ (GCNIS) arise from primary germ cells (PGC) or gonocytes. PGCs develop from the epiblast and, as with gonocytes, they express pluripotent stem cell markers, e.g., KIT, NANOG. The presence of SRY will orient the differentiation into ovaries or testes. Under normal conditions, these markers progressively decrease and are replaced by markers of germ-cell commitment such as VASA and TSPY. Germ cell tumors regain the expression of stem cell- and pluripotency markers of gonocytes (e.g., OCT3/4, NANOG). GCNIS give rise to seminomas, and non-seminomas (e.g., yolk sac tumors, teratomas) differentiate from embryonic cell carcinomas.8
The tumor microenvironment (TME)
Tumorigenesis is a complex process driven by both genetic and metabolic alterations in neoplastic cells and the microenvironment surrounding these cells. TME includes blood and lymph vessels; and mesenchymal and immune cells. TME is a major contributor to tumor progression and therapy outcome. TME characteristics have been linked to response or resistance to therapy with high infiltration of cytotoxic T cells supporting a better immune response to attack tumor cells.
TME is composed of the tumor itself, associated with all its interacting cells and cellular processes—cancer stem cells, infiltrating immune cells, blood vessels that carry nutrients and signaling molecules—as well as extracellular matrix (ECM), which allows migration of cancer cells to other sites.9
The tumor immune microenvironment (TIME)
The immune signatures associated with different types of cancers have been uncovered based on genetic analyses of The Cancer Genomic Atlas (TCGA) samples, and a few common immune subtypes of cancers have been revealed. Three classes of TIME10 are described—infiltrated-excluded (IE), infiltrated-inflamed (II) and infiltrated-tertiary lymphoid structure (TLS).
How do cancer cells shape their microenvironment?
In order to thrive, cancer cells require a well-vascularized, tolerant environment with sufficient nutrients. Cancer cells actively shape this environment to favor their growth and to protect themselves from threats from the immune system by inducing dendritic cells to exhibit tolerogenic characteristics.11